Systems and methods for ocular laser surgery and therapeutic treatments

ABSTRACT

Systems, devices and methods are provided to deliver microporation medical treatments to improve biomechanics, wherein the system includes a laser for generating a beam of laser radiation on a treatment-axis not aligned with a patient&#39;s visual-axis, operable for use in subsurface ablative medical treatments to create an array pattern of micropores that improves biomechanics. The array pattern of micropores is at least one of a radial pattern, a spiral pattern, a phyllotactic pattern, or an asymmetric pattern.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/942,513, filed Mar. 31, 2018, which claims priority to U.S.Provisional Appl. No. 62/480,294, filed Mar. 31, 2017 and titled“SYSTEMS AND METHODS FOR OCULAR LASER SURGERY AND THERAPEUTICTREATMENTS,” the entire contents and disclosures of which are herebyincorporated by reference.

This application is related to the subject matter disclosed in U.S.Appl. No. 61/798,379, filed Mar. 15, 2013; U.S. Appl. No. 60/662,026,filed Mar. 15, 2005; U.S. application Ser. No. 11/376,969, filed Mar.15, 2006; U.S. Appl. No. 60/842,270, filed Sep. 5, 2006; U.S. Appl. No.60/865,314, filed Nov. 10, 2006; U.S. Appl. No. 60/857,821, filed Nov.10, 2006; U.S. application Ser. No. 11/850,407, filed Sep. 5, 2007; U.S.application Ser. No. 11/938,489, filed Nov. 12, 2007; U.S. applicationSer. No. 12/958,037, filed Dec. 1, 2010; U.S. application Ser. No.13/342,441, filed Jan. 3, 2012; U.S. application Ser. No. 14/526,426,filed Oct. 28, 2014; U.S. application Ser. No. 14/861,142, filed Sep.22, 2015; U.S. application Ser. No. 11/850,407, filed Sep. 5, 2007; U.S.application Ser. No. 14/213,492, filed Mar. 14, 2014; and to U.S. Appl.No. 62/356,457, filed Jun. 29, 2016; U.S. Appl. No. 62/356,467, filedJun. 29, 2016, each of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The subject matter described herein relates generally to systems,methods, therapies and devices for laser scleral microporation, and moreparticularly for to systems, methods and devices for laser scleralmicroporation rejuvenation of tissue of the eye, specifically regardingaging of connective tissue, rejuvenation of connective tissue by ocularor scleral rejuvenation.

BACKGROUND OF THE INVENTION

The eye is a biomechanical structure, a complex sense organ thatcontains complex muscular, drainage, and fluid mechanisms responsiblefor visual function and ocular biotransport. The accommodative system isthe primary moving system in the eye organ, facilitating manyphysiological and visual functions in the eye. The physiological role ofthe accommodation system is to move aqueous, blood, nutrients, oxygen,carbon dioxide, and other cells, around the eye organ. In general, theloss of accommodative ability in presbyopes has many contributinglenticular, as well as extralenticular and physiological factors thatare affected by increasing age. Increasing ocular rigidity with ageproduces stress and strain on these ocular structures and can affectaccommodative ability which can impact the eye in the form of decreasedbiomechanical efficiency for physiological processes including visualaccommodation, aqueous hydrodynamics, vitreous hydrodynamics and ocularpulsatile blood flow to name a few. Current procedures only manipulateoptics through some artificial means such as by refractive lasersurgery, adaptive optics, or corneal or intraocular implants whichexchange power in one optic of the eye and ignore the other optic andthe importance of preserving the physiological functions of theaccommodative mechanism.

Additionally, current implanting devices in the sclera obtain themechanical effect upon accommodation. They do not take into accounteffects of ‘pores’, ‘micropores’, or creating a matrix array of poreswith a central hexagon, or polygon in 3D tissue. As such, currentprocedures and devices fail to restore normal ocular physiologicalfunctions.

Accordingly, there is a need for systems and methods for restoringnormal ocular physiological functions taking into account effects of‘pores’ or creating a lattice or matrix array of pores with a centralhexagon or polygon in three dimensional (3D) tissue.

SUMMARY OF THE INVENTION

Disclosed are systems, devices and methods for laser scleralmicroporation for rejuvenation of tissue of the eye, specificallyregarding aging of connective tissue, rejuvenation of connective tissueby scleral rejuvenation. The systems, devices and methods disclosedherein restore physiological functions of the eye including restoringphysiological accommodation or physiological pseudo-accommodationthrough natural physiological and biomechanical phenomena associatedwith natural accommodation of the eye.

In some embodiments, a system is provided to deliver microporationmedical treatments to improve biomechanics, wherein the system includesa laser for generating a beam of laser radiation on a treatment-axis notaligned with a patient's visual-axis, operable for use in subsurfaceablative medical treatments to create an array or lattice pattern ofmicropores that improves biomechanics. The system includes a housing, acontroller within the housing, in communication with the laser andoperable to control dosimetry of the beam of laser radiation inapplication to a target tissue. The system also includes a lens operableto focus the beam of laser radiation onto a target tissue, and anautomated off-axis subsurface anatomy tracking, measuring, and avoidancesystem. The array pattern of micropores is at least one of a radialpattern, a spiral pattern, a phyllotactic pattern, or an asymmetricpattern.

In some embodiments, the array pattern of micropores is a spiral patternof an Archimedean spiral, a Euler spiral, a Fermat's spiral, ahyperbolic spiral, a lituus, a logarithmic spiral, a Fibonacci spiral, agolden spiral, a Bravais lattice, a non Bravais lattice, or combinationsthereof.

In some embodiments, the array pattern of micropores has a controlledasymmetry which is an at least partial rotational asymmetry about thecenter of the array pattern. The at least partial rotational asymmetrymay extend to at least 51 percent of the micropores of the arraypattern. The at least partial rotational asymmetry may extend to atleast 20 micropores of the array pattern. In some embodiments, the arraypattern of micropores has a random asymmetry.

In some embodiments, the array pattern of micropores has a controlledsymmetry which is an at least partial rotational symmetry about thecenter of the array pattern. The at least partial rotational symmetrymay extend to at least 51 percent of the micropores of the arraypattern. The at least partial rotational symmetry may extend to at least20 micropores of the array pattern. In some embodiments, the arraypattern of micropores may have a random symmetry.

In some embodiments, the array pattern has a number of clockwise spiralsand a number of counter-clockwise spirals. The number of clockwisespirals and the number of counterclockwise spirals may be Fibonaccinumbers or multiples of Fibonacci numbers, or they may be in a ratiothat converges on the golden ratio.

In some embodiments, a method is provided for delivering microporationmedical treatments to improve biomechanics. The method includesgenerating, by a laser, a treatment beam on a treatment-axis not alignedwith a patient's visual-axis in a subsurface ablative medical treatmentto create an array of micropores that improves biomechanics;controlling, by a controller in electrical communication with the laser,dosimetry of the treatment beam in application to a target tissue;focusing, by a lens, the treatment beam onto the target tissue;monitoring, by an automated off-axis subsurface anatomy tracking,measuring, and avoidance system, an eye position for application of thetreatment beam; and wherein the array pattern of micropores is at leastone of a radial pattern, a spiral pattern, a phyllotactic pattern, or anasymmetric pattern.

BRIEF DESCRIPTION OF THE DRAWING(S)

The details of the subject matter set forth herein, both as to itsstructure and operation, may be apparent by study of the accompanyingfigures, in which like reference numerals refer to like parts. Thecomponents in the figures are not necessarily to scale, emphasis insteadbeing placed upon illustrating the principles of the subject matter.Moreover, all illustrations are intended to convey concepts, whererelative sizes, shapes and other detailed attributes may be illustratedschematically rather than literally or precisely. Illustrated in theaccompanying drawing(s) is at least one of the best mode embodiments ofthe present invention.

FIGS. 1A-1 to 1A-3 illustrate exemplary scleral laser rejuvenation ofviscoelasticity, according to an embodiment of the disclosure.

FIGS. 1A-4 to 1A-5 illustrate exemplary posterior scleral rejuvenationand treatment zones, according to an embodiment of the disclosure.

FIGS. 1A-6-1A-7 illustrate exemplary posterior scleral rejuvenation andocular nerve head decompression, according to an embodiment of thedisclosure.

FIGS. 1B to 1E illustrate exemplary pore matrix arrays, according to anembodiment of the disclosure.

FIG. 1E-1 illustrates exemplary coagulation zones, according to anembodiment of the disclosure.

FIG. 1E-2 illustrates an exemplary pattern speed calculation, accordingto an embodiment of the disclosure.

FIGS. 1F(a) to 1F(c) illustrate exemplary schematic projections of abasal plane of the hcp unit cell on close packed layers, according to anembodiment of the disclosure.

FIGS. 1G-1 to 1G-3 illustrate exemplary laser profiles, according to anembodiment of the disclosure.

FIG. 1G-4 illustrates exemplary chart of thermal damage zone (TDZ),according to an embodiment of the disclosure.

FIG. 1H illustrates exemplary pore structure characteristics, accordingto an embodiment of the disclosure.

FIGS. 2A-1 to 2A-2 illustrate an exemplary treatment pattern with threecritical zones, according to an embodiment of the disclosure.

FIGS. 2B-1 to 2B-3 illustrate an exemplary treatment pattern with fivecritical zones, according to an embodiment of the disclosure.

FIGS. 2C-1 to 2C-4 illustrate exemplary laser scleral uncrosslinking ofscleral fibrils and microfibrils, according to an embodiment of thedisclosure.

FIGS. 2D-1 to 2D-4 illustrate exemplary effect of treatment on ocularrigidity, according to an embodiment of the disclosure.

FIGS. 2E(a) and 2E(b) illustrate another exemplary three critical zonesof significance, according to an embodiment of the disclosure.

FIG. 2F illustrates an exemplary matrix array of micro-excisions in fouroblique quadrants, according to an embodiment of the disclosure.

FIG. 2G illustrates an exemplary graphical representation of treatmentresults, according to an embodiment of the disclosure.

FIG. 2H illustrates an exemplary box-and-whiskers plot of the ocularrigidity, according to an embodiment of the disclosure.

FIG. 2I illustrates an exemplary box-and-whiskers plot of pre- andpost-operative intraocular pressure, according to an embodiment of thedisclosure.

FIG. 2J illustrates exemplary charts showing uncorrected anddistance-corrected visual acuity, according to an embodiment of thedisclosure.

FIG. 2K-1 illustrates an exemplary protocol execution, according to anembodiment of the disclosure.

FIGS. 2K-1-A to 2K-1-C illustrate exemplary protocol parameters forthree critical zones, according to an embodiment of the disclosure.

FIGS. 2K-2 to 2K-17 illustrate exemplary views of various protocols andtheir results, according to an embodiment of the disclosure.

FIGS. 2K-18 to 2K-19 illustrate other exemplary microporation patterns,according to an embodiment of the disclosure.

FIG. 2K-20 illustrates another exemplary pattern, according to anembodiment of the disclosure.

FIG. 3A illustrates an exemplary laser treatment system, according to anembodiment of the disclosure.

FIG. 3B illustrates another exemplary laser treatment system, accordingto an embodiment of the disclosure.

FIG. 3C illustrates an exemplary camera correction system, according toan embodiment of the disclosure.

FIG. 3D illustrates an exemplary flow diagram of a camera-based eyetracker process, according to an embodiment of the disclosure.

FIG. 4A illustrates another exemplary laser treatment system, accordingto an embodiment of the disclosure.

FIGS. 4A-(1-10) illustrate how microporation/nanoporation may be used,according to an embodiment of the disclosure.

FIG. 4B-1 illustrates another exemplary laser treatment system,according to an embodiment of the disclosure.

FIG. 4B-2 illustrates an exemplary diagram of an ablation pore in thesclera showing an example of the depth of an ablation, according to anembodiment of the disclosure.

FIG. 5 illustrates an exemplary flow diagram of OCT-based depth control,according to an embodiment of the disclosure.

FIG. 6 illustrates an exemplary laser treatment system component map,according to an embodiment of the disclosure.

FIG. 7 illustrates another exemplary laser treatment system, accordingto an embodiment of the disclosure.

FIG. 7-1 illustrates another exemplary laser treatment system, accordingto an embodiment of the disclosure.

FIG. 8 illustrates exemplary orthogonal projections, according to anembodiment of the disclosure.

FIG. 9 illustrates exemplary 3D mapping, according to an embodiment ofthe disclosure.

FIG. 10 illustrates exemplary design patterns, according to anembodiment of the disclosure.

FIG. 11 illustrates exemplary models, according to an embodiment of thedisclosure.

FIG. 12 illustrates an exemplary schematized representation ofmicroporation, according to an embodiment of the disclosure.

FIG. 13 illustrates an exemplary graphical image of microporation,according to an embodiment of the disclosure.

FIG. 14A illustrates an exemplary microporation pattern, according to anembodiment of the disclosure.

FIG. 14B is an exemplary illustration of a phyllotactic spiral pattern,according to an embodiment of the disclosure.

FIG. 14C is another exemplary illustration of another phyllotacticspiral pattern, according to an embodiment of the disclosure.

FIGS. 14D and 14E are exemplary illustrations of the Vogel model,according to an embodiment of the disclosure.

FIGS. 15A-15F are exemplary illustrations of other phyllotactic spiralpatterns, according to an embodiment of the disclosure.

FIGS. 16A-16N are exemplary illustrations of exemplary microporationpatterns derived from icosahedron pattern shapes, according to anembodiment of the disclosure.

FIGS. 17A-17B are exemplary illustrations of other microporationpatterns derived from icosahedron pattern shapes, according to anembodiment of the disclosure.

FIG. 18 is an exemplary lens design, according to an embodiment of thedisclosure.

FIG. 19 illustrates another exemplary microporation system, according toan embodiment of the disclosure.

FIGS. 20 and 20A to 20C illustrate exemplary views of a docking station,according to an embodiment of the disclosure.

FIG. 20D illustrates an exemplary scleral fixation component, accordingto an embodiment of the disclosure.

FIGS. 20E to 20H illustrate different exemplary views of off axisscanning, according to an embodiment of the disclosure.

FIG. 20I illustrates exemplary off axis scanning with treatment beingangular, according to an embodiment of the disclosure.

FIG. 20J illustrates the aqueous flow within the eye.

FIGS. 20K to 20L illustrate exemplary increase in uveal outflow,according to an embodiment of the disclosure.

FIG. 20M illustrates an exemplary hand piece delivery system, accordingto an embodiment of the disclosure.

FIGS. 20N to 20O illustrate exemplary treatment zones in the anteriorand posterior globe, according to an embodiment of the disclosure.

FIGS. 20P-1 to 20P-3 illustrate exemplary targets for drug delivery,according to an embodiment of the disclosure.

FIGS. 20Q-1 to 20Q-3 illustrate an exemplary drug delivery, according toan embodiment of the disclosure.

FIG. 20R illustrates an exemplary opthacoil, according to an embodimentof the disclosure.

FIG. 20S illustrates exemplary drug delivery carriers, according to anembodiment of the disclosure.

FIGS. 20T-1 to 20T-3 illustrate an exemplary scleral wafer, according toan embodiment of the disclosure.

FIGS. 21A and 21B illustrate an exemplary a nozzle guard, according toan embodiment of the disclosure.

FIG. 22 illustrates an exemplary nozzle guard being attached to anozzle, according to an embodiment of the disclosure.

FIG. 23 illustrates the nozzle being fitted with disposable insert andfilter, according to an embodiment of the disclosure.

FIG. 24 illustrates an exemplary workstation, according to an embodimentof the disclosure.

FIGS. 25A and 25B illustrate the housing unit which is rotatable 360degrees, according to an embodiment of the disclosure.

FIG. 26-A illustrates an exemplary multilayer imaging platform,according to an embodiment of the disclosure.

FIGS. 26-B and 26-C illustrate an exemplary CCD camera, according to anembodiment of the disclosure.

FIG. 26-D illustrates an exemplary camera view using a CCD camera,according to an embodiment of the disclosure.

FIG. 26-1 illustrates another exemplary laser system, according to anembodiment of the disclosure.

FIG. 26-2 illustrates exemplary chart for wavelengths with high waterabsorption, according to an embodiment of the disclosure.

FIGS. 26-3A, 26-3A1 and 26-3A2 illustrate exemplary treatmentparameters, according to an embodiment of the disclosure.

FIG. 26-4 illustrates anatomy recognition, according to an embodiment ofthe disclosure.

FIG. 26-4-1 illustrates an exemplary effect of treatment density,according to an embodiment of the disclosure

FIG. 26-5 illustrates another exemplary workstation, according to anembodiment of the disclosure.

FIGS. 27A to 27C illustrate exemplary lens/mask, according to anembodiment of the disclosure.

FIGS. 28A to 28C and FIGS. 29A to 29B illustrate an exemplary speculumand exemplary operation using the speculum, according to an embodimentof the disclosure.

FIG. 30 illustrates an exemplary test and anatomy avoidance in a lasersystem, according to an embodiment of the disclosure.

FIG. 31 and FIG. 32 illustrate further exemplary treatment parameters,according to an embodiment of the disclosure.

FIG. 33 illustrates exemplary treatment region shapes, according to anembodiment of the disclosure.

FIG. 34 illustrates exemplary effect of shape treatment, according to anembodiment of the disclosure.

FIG. 35 and FIG. 36 illustrate exemplary therapy simulation methods,according to an embodiment of the disclosure.

FIGS. 37-39 illustrate exemplary effects of volume fraction, accordingto an embodiment of the disclosure.

FIG. 40 illustrates another exemplary nozzle, according to an embodimentof the disclosure.

FIG. 41 illustrates exemplary model outcomes, according to an embodimentof the disclosure.

DETAILED DESCRIPTION

The below described figures illustrate the described invention andmethod of use in at least one of its preferred, best mode embodiment,which is further defined in detail in the following description. Thosehaving ordinary skill in the art may be able to make alterations andmodifications to what is described herein without departing from itsspirit and scope. While this invention is susceptible of embodiment inmany different forms, there is shown in the drawings and will herein bedescribed in detail a preferred embodiment of the invention with theunderstanding that the present disclosure is to be considered as anexemplification of the principles of the invention and is not intendedto limit the broad aspect of the invention to the embodimentillustrated. All features, elements, components, functions, and stepsdescribed with respect to any embodiment provided herein are intended tobe freely combinable and substitutable with those from any otherembodiment unless otherwise stated. Therefore, it should be understoodthat what is illustrated is set forth only for the purposes of exampleand should not be taken as a limitation on the scope of the presentinvention.

FIGS. 1 to 41 illustrate exemplary embodiments of systems and methodsfor laser scleral microporation for rejuvenation of tissue of the eye,specifically regarding aging of connective tissue, rejuvenation ofconnective tissue by scleral rejuvenation.

Generally, the systems and methods of the present disclosure take intoconsideration combination of pores filling technique and creatingmatrices of pores in three dimensions (3D). Pores with a particulardepth, size and arrangement in a matrix 3D scaffold of tissue produceplastic behavior within the tissue matrix. This affects thebiomechanical properties of the scleral tissue allowing it to be morepliable. It is known that connective tissues that contain elastin are‘pliable’ and meant to have elasticity. The sclera in fact has naturalviscoelasticity.

Influence of ocular rigidity and ocular biomechanics on the pathogenesisof age-related presbyopia is an important aspect herein. Descriptionsherein are made to modifying the structural stiffness of the ocularconnective tissues, namely the sclera of the eye using the systems andmethods of the present disclosure.

In order to better appreciate the present disclosure, ocularaccommodation, ocular rigidity, ocular biomechanics, and presbyopia willbe briefly described. In general, the loss of accommodative ability inpresbyopes has many contributing lenticular, as well as extralenticularand physiological factors that are affected by increasing age.Increasing ocular rigidity with age produces stress and strain on theseocular structures and can affect accommodative ability. Overall,understanding the impact of ocular biomechanics, ocular rigidity, andloss of accommodation could produce new ophthalmic treatment paradigms.Scleral therapies may have an important role for treating biomechanicaldeficiencies in presbyopes by providing at least one means of addressingthe true etiology of the clinical manifestation of the loss ofaccommodation seen with age. The effects of the loss of accommodationhas impact on the physiological functions of the eye to include but notlimited to visual accommodation, aqueous hydrodynamics, vitreoushydrodynamics, and ocular pulsatile blood flow. Using the systems andmethods of the present disclosure to restore more pliable biomechanicalproperties of ocular connective tissue is a safe procedure and canrestore accommodative ability in aging adults.

Accommodation has traditionally been described as the ability of thecrystalline lens of the eye to change dioptric power dynamically toadjust to various distances. More recently, accommodation has beenbetter described as a complex biomechanical system having bothlenticular and extralenticular components. These components actsynchronously with many anatomical and physiological structures in theeye organ to orchestrate not only the visual manifestations that occurwith accommodation, but also the physiological functions integral to theeye organ, such as aqueous hydrodynamics and ocular biotransport.

Biomechanics is the study of the origin and effects of forces inbiological systems. Biomechanics has remained underutilized inophthalmology. This biomechanical paradigm deserves to be extended tothe anatomical connective tissues of the intricate eye organ.Understanding ocular biomechanics as it relates to accommodation canallow for a more complete picture of the role this primary moving systemhas on overall eye organ function, while maintaining optical quality forvisual tasks.

The eye is a biomechanical structure, a complex sense organ thatcontains complex muscular, drainage, and fluid mechanisms responsiblefor visual function and ocular biotransport. The accommodative system isthe primary moving system in the eye organ, facilitating manyphysiological and visual functions in the eye. The physiological role ofthe accommodation system is to move aqueous, blood, nutrients, oxygen,carbon dioxide, and other cells, around the eye organ. In addition, itacts as a neuroreflexive loop, responding to optical informationreceived through the cornea and lens to fine tune focusing powerthroughout a range of vision, and is essentially the “heart” of the eyeorgan.

Biomechanics is particularly important to the complexity ofaccommodative function and dysfunction which occurs with age-related eyediseases (e.g., presbyopia, glaucoma, age-related macular degeneration(AMD) and myopia. Age-related changes in the crystalline lens have longbeen understood and reported. Recent endeavors have demonstrated howstiffening ocular tissues manifest as presbyopia. Ocular rigidity hasbeen correlated with a clinically significant loss of accommodation withage, age-related macular degeneration, increased intraocular pressure(IOP), decreased ocular pulsatile blood, and certain forms of glaucomaand cataracts. Stiffening of the zonular apparatus and loss ofelasticity of the choroid may also contribute to accommodation.

Biomechanics plays a critical role in the pathophysiology of the eyeorgan. In healthy young eyes, this mechanism is biomechanicallyefficient and precisely achieves the focusing of objects at a particulardistance. As we age, however, this biomechanical mechanism is affectedby changes in material properties, anatomical relationships, anddegradation of healthy connective tissue infrastructural relationshipsdue to the aging process. These biomechanical dysfunctions result in adisruption of the functions of not only the accommodative mechanism,which affect the ability to dynamically focus the lens for ideal opticalimage quality, but also the functions of other physiologic mechanismscritical to the eye organ such as ocular biofluidics, ocular blood flow,and metabolic homeostasis. Thus, biomechanics plays a key role in thepathophysiology that occurs with aging, including glaucoma and AMD.

Presbyopia is a condition of sight traditionally defined as theprogressive loss of accommodative ability with age. The loss of theability to adjust the dioptric power of the lens for various distances,however, is only one consequence of this complex condition. As the eyeages, there are connective tissues changes in the eye organ or “oculus”that produce significant but reversible impacts on the biomechanicalefficiencies of ocular function. Studies using ultrasound biomicroscopy(UBM) and endoscopy, optical coherence tomography (OCT), and magneticresonance imaging (MRI) have shown age-related changes in the vitreousmembrane, peripheral choroid, ciliary muscle, and zonules. Age-relatedchanges create biomechanical alterations that also manifest in thesclera, which bows inward with increasing age.

According to one model, during accommodation the ciliary musclecontracts, releasing tension on the zonules, which reduces tension onthe lens and allows it to curve and increase its refractive power. Thedecrease in lens elasticity with age impedes the deformation of the lensand the lens refractive power will not increase enough to see objects atnear. Current approaches to resolve the loss of near vision symptoms ofpresbyopia typically included spectacles, multifocal or monovisioncontact lenses, corneal procedures to induce monovision ormultifocality, lens implants using multifocal lenses, corneal inlays,onlays, and accommodating intraocular lenses. However, none of theseprocedures restore true accommodation. Instead, these procedures attemptto improve near and intermediate vision by manipulating optics either inthe cornea or in the lens.

For true physiological accommodation to occur, the eye must modify itsfocal length to see objects clearly when changing focus from far to nearor from near too far. Generally, this is thought to be caused primarilyby the ciliary muscles, which contract and force the lens into a moreconvex shape. However, the accommodation process is far more complex.Accommodation is also influenced by corneal aberrations, and thus to seeclearly, the lens must be molded and undulated to corneal aberrations,creating a balance of the optics between the lens and the cornea beforeexerting a focal response to accommodative stimulus. In addition, thezonular tensions on the lens and the elastic choroid contribute to theaccommodative range and biomechanical functionality of the entireaccommodation complex. The malfunction of these complex componentscreates a biomechanical relationship dysfunction, which can affect theaccommodative amplitude, lens deformation, and the central optical powergenerated from dynamic accommodative forces.

Scleral surgery, e.g., as a treatment for presbyopia has used cornealincisions to treat myopia, a treatment known as radial keratotomy (RK).Anterior ciliary sclerotomy (ACS) procedure was developed, whichutilized radial incisions in the sections of the sclera overlaying theciliary muscle. The incisions were thought to increase the space betweenthe ciliary muscle and the lens, allowing for increased ‘workingdistance’ for the muscles and tightening of the zonules to restore theaccommodative ability in presbyopes. The long-term results of ACSsuggest that the procedure was largely unsuccessful at restoringaccommodation and the effects were eliminated completely as the scleralwounds healed very quickly. Laser presbyopia reversal (LAPR) followedfrom ACS, using lasers to perform radial sclerectomy. The results ofLAPR, however, were mixed. Scleral implants attempt to lift the ciliarymuscle and the sclera, tightening the zonules holding the lens, andrestore accommodative ability. Their effectiveness remainscontroversial.

Accommodation loss and presbyopia have been used interchangeably.However, it should be emphasized that accommodation loss is just oneclinical manifestation of the consequences of an aging (or presbyopic)eye. With increasing age, there are numerous changes to the lens andsurrounding tissues, which may contribute to accommodation loss.Research has shown that the lens substance stiffens with age, decreasingits ability to change shape (and refractive power) during accommodation,and decreasing accommodative ability. The softening of the lens capsule,flattening of the lens, and lens movement anteriorly with age may alsocontribute to the loss of accommodative ability, however, accommodationis a complex mechanism. Many lenticular-based models fail to incorporateeffects from the extralenticular structures. To understand accommodationfully, both lenticular and extralenticular components need to beconsidered together.

The amount of accommodation lost with age, which is related toextralenticular factors (primarily the zonules, choroid, and sclera) hasonly been relatively recently investigated. The circumlental spacedecreases with age. The ciliary body has been shown to contract duringaccommodation, and there is a decrease in the distance from scleral spurto the ora serrata. Using UBM, an attachment zone of the posteriorzonules adjacent to the ora serrata has been identified, and contractionof these zonules is thought to be the etiology of the decrease indistance found with accommodation. This complex action of the zonules issuspected to be reciprocal. While the anterior zonules relax, reducingtheir tension on the lens such that the lens changes shape anteriorly,the posterior zonules contract, moving the posterior capsule backward.This vitreal-zonular complex stiffens with age, losing its elasticity.It is also now known that the sclera becomes less deformable duringaccommodation in the nasal area with age. The vitreous has also beensuggested as an important factor to lens shape changes duringaccommodation and may have a role in presbyopia. New models suggest upto 3 diopters that might be contributed by extralenticular structures.The age-related changes in these structures and their biomechanicalinteractions with the ciliary-lens complex may contribute to presbyopia.

The ciliary muscle plays a critical role in many functions of the eyeorgan including accommodation and aqueous hydrodynamics (outflow/inflow,pH regulation, and IOP). An optically significant role of the ciliarymuscles is to adjust the lens dynamically to focus at various distances(near, intermediate, and far). During accommodation, the ciliary musclecontracts to change the shape of the lens and, in basic terms, moves thelens forward and inwards. This shape deformation is caused by therelease of tension on the anterior zonules and by the aqueous fluidmoving in the posterior chamber. This allows the lens to change from arelatively aspherical shape to a more spherical shape, therebyincreasing its refractive power for near vision. Contraction of theciliary muscle is also important for spreading the trabecular meshworkand aqueous drainage. Inadequate drainage or a cause of perturbance tothe normal flow of aqueous drainage either by uveal outflow pathway orSchlemm's canal can increase IOP and contribute to the development ofcertain types of ocular hypertension or glaucoma. Ciliary musclecontraction during accommodation lowers intraocular pressure (IOP). Thisis likely due to a decrease in aqueous outflow resistance duringaccommodation, caused by the ciliary muscle moving inward andanteriorly, which dilates Schlemm's canal and opens the trabecularmeshwork.

FIGS. 1A-1 to 1A-3 illustrate, in some embodiments, exemplary sclerallaser rejuvenation of viscoelasticity allowing compliance for theciliary muscle to exert force on the lens. The ciliary muscle and itscomponents include the meridional or longitudinal (1), radial or oblique(2), and circular or sphincteric (3) layers of muscle fibres, asdisplayed by successive removal towards the ocular interior. The corneaand sclera have been removed, leaving the canal of Schlemm (a),collecting venules (b) and scleral spur (c). The meridional fibres (1)often display acutely angled junctions (d) and terminate in epichoroidalstars (e). The radial fibres meet at obtuse angles (f) and similarjunctions, at even wider angles (g), occur in the circular ciliarymuscle.

The rigidity of a structure describes its resistance to deformation and,in the case of a confined structure with incompressible contents,rigidity is related to the structure's volume and the pressure of thecontents. Ocular rigidity refers to the resistance of the eyeball tostresses. Increases in ocular rigidity have been correlated withincreasing age, lending support to the idea that presbyopia and ocularrigidity share a common biomechanical factor. In addition to affectingaccommodation, ocular rigidity may also hinder the accommodationapparatus to return to a disaccommodated state, following anaccommodated state, by dampening the elastic recoil of the choroidposteriorly.

Ocular rigidity has been correlated with decreased ocular pulsatileblood flow. The blood vessels that support the health of the entire eyepass through the sclera. An increase in ocular rigidity could increasescleral resistance to venous outflow and decrease the flow throughchoroidal vessels.

Ocular rigidity has been correlated to the pathogenesis of maculardegeneration. An increase in ocular rigidity could increase scleralresistance to venous outflow and decrease the flow through choroidalvessels. This may compromise Bruch's membrane and lead to choroidalneovascularization. Decrease flow through the choroidal vessels may alsodecrease perfusion, which could lead to induced hypoxia and choroidalneovascularization.

Ocular rigidity has been correlated with certain forms of glaucoma.Recent models suggest that ocular rigidity affects the scleral responseto increased intraocular pressure. Reducing ocular rigidity may decreasethe mechanical strain that is transferred to the optic nerve head withelevated intraocular pressure due to age-related changes and ocularrigidity in both the anterior and posterior globe. During normalaccommodation the retina and choroid are pulled forward near the opticnerve head when the ciliary muscle contracts. The ciliary muscle retainsits contractile force with age, however increased rigidity of the scleramay affect ciliary muscle motility, which could increase the tensionalforces on the optic nerve head during ciliary muscle contraction.

FIGS. 1A-4-1A-7 illustrate in some embodiments posterior scleralrejuvenation and ocular nerve head decompression.

Ocular rigidity or “stiffness” of the outer ocular structures of the eyeincluding the sclera and the cornea, which occurs in the oculus withage, effects the biomechanical functions of all the internal anatomicalstructures, such as the extralenticular and lenticular anatomy of theaccommodation complex as well as the trabecular meshwork, the choroidand the retina. In addition, ocular rigidity has a significant impact onthe physiological functions of the eye organ, such as a change in theefficiency of aqueous dynamics and ocular pulsatile blood flow.Increased ocular rigidity affects other tissues as well, includingocular blood flow through the sclera and optic nerve. Ocular rigidityhas been correlated to the pathogenesis many age-related eye diseases.Therefore, ocular rigidity may not only impact the loss of visualaccommodation but also have more extensive clinical significance.

Ocular biomechanics is the study of the origin and effects of forces inthe eye. All ocular tissues contain collagen, which provides them withviscoelastic properties. Viscoelastic substances contain the propertiesof both fluids and elastic materials. Fluids tend to take the shape oftheir container, while elastic materials can deform under a stress andreturn to their original form. When a stress is applied to viscoelasticmaterials, the molecules will rearrange to accommodate the stress, whichis termed creep. This rearrangement also generates back stresses in thematerial that allow the material to return to its original form when thestress is removed. Thus, viscoelasticity is an important property thatallows tissues to respond to stresses.

Chronic stress that exceeds the healing ability of tissues can lead tochronic inflammation and eventual cell death, which technicallydescribes the pathophysiology of aging. Ocular connective tissues areimpacted, like all other connective tissues, by age. The scleraconstitutes 5/6 of the oculus and is made up of dense irregularconnective tissue. It is comprised primarily of collagen (50-75%),elastin (2-5%), and proteoglycans. The connective tissues of the eyestiffen with increasing age, losing their elasticity, largely due to thecrosslinking that occurs with age. Crosslinks are bonds between polymerchains, such as those in synthetic biomaterials or the proteins inconnective tissues. Crosslinking can be caused by free radicals,ultraviolet light exposure, and aging. In connective tissues, collagenand elastin can crosslink to continuously form fibrils and microfibrilsover time. With increasing amounts of fibrils and microfibrils, thesclera stiffens, undergoing a ‘sclerosclerosis’, as well as aconcomitant increase in metabolic physiological stress. As mentionedpreviously, age- and race-related increases in collagen crosslinks,along with loss of elastin-driven recoil, and/or collagenmicroarchitectural changes, may underlie the change in scleral materialproperties leading to loss of compliance of scleral tissue when stressis applied. As this pathophysiology progresses, the sclera exertscompression and loading stresses on underlying structures, creatingbiomechanical dysfunction, specifically those related to accommodation.

Age-related increased ocular rigidity also has an impact on the ciliarymuscle and the biomechanics of the accommodation mechanism. For example,it is known that the contractile power of the ciliary muscle does notdecrease with age, however, it may have a decreased capability tocontract or exert substantial forces on the lens to create the samedioptric changes as those in a youthful system. A further explanationmay be that ocular rigidity affects the biomechanical contributions ofthe ciliary muscle by relaxing zonular tension and decreasingaccommodative ability.

Age-related material property changes within the sclera affects themobility of connective tissues of the scleral fibers, directly leadingto the loss of compliance. This causes a decrease in the normalmaintenance and turnover of proteoglycans (PG) in the sclera, leading tothe loss of PG and eventual tissue atrophy. However, if the complianceand mobility of scleral connective tissues are restored, this PG losscan be reversed.

As mentioned above, the systems and methods of the present disclosuretake into consideration combination of pores filling technique andcreating matrices of pores in three dimensions. Pores with a specificdepth, size and arrangement in a matrix 3D scaffold of tissue produceplastic behavior within the tissue matrix. This affects thebiomechanical properties of the scleral tissue allowing it to be morepliable. The plurality of pores may be created in a matrix 3D scaffold,in an array pattern or a lattice(s). Various microporationcharacteristics may be supported. These may include volume, depth,density, and so on.

It is advantageous to create a tetrahedral or central hexagon shape. Inorder to create a central hexagon within a matrix there must be a seriesof ‘pores’ with specific composition, depth, and relationship to theother ‘pores’ in the matrix and spatial tissue between the pores in thematrix. A substantial amount of depth (e.g., at least 85%) of the tissueis also needed to gain the full effect of the entire matrix throughoutthe dimensions of the polygon. The matrix within the tissue contains apolygon. The central angle of a polygon stays the same regardless of theplurality of spots within the matrix. This is an essential component ofthe systems and methods of the present disclosure since they takeadvantage of a matrix with a polygon which includes the uniquerelationship and properties of the pore pattern in the matrix orlattice.

The central angle of a polygon is the angle subtended at the center ofthe polygon by one of its sides. Despite the number of sides of thepolygon, the central angle of the polygon remains the same.

Current implanting devices in the sclera obtain the mechanical effectupon accommodation. No current devices or methods take into account theeffects of ‘pores’ or creating a matrix array of pores with a centralhexagon or polygon in 3D tissue. The systems and methods of the currentdisclosure may create a pore matrix array in biological tissue to allowthe change in the biomechanical properties of the tissue itself tocreate the mechanical effect upon biological functions of the eye. Aprimary requirement of the ‘pores’ in the matrix is the polygon.

A polygon by definition can have any number of sides and the area,perimeter, and dimensions of the polygon in 3D can be mathematicallymeasured. In a regular polygon case the central angle is the angle madeat the center of the polygon by any two adjacent vertices of thepolygon. If one were to draw a line from any two adjacent vertices tothe center, they would make the central angle. Because the polygon isregular, all central angles are equal. It does not matter which side onechooses. All central angles would add up to 360° (a full circle), so themeasure of the central angle is 360 divided by the number of sides. Or,as a formula:

Central Angle=360/n degrees, where n is the number of sides.

The measure of the central angle thus depends only on the number ofsides, not the size of the polygon.

As used herein, polygons are not limited to “regular” or “irregular.”Polygons are one of the most all-encompassing shapes in geometry. Fromthe simple triangle, up through squares, rectangles, trapezoids, tododecagons and beyond.

Types of polygons include regular and irregular, convex and concave,self-intersecting and crossed. Regular polygons have all sides andinterior angles the same. Regular polygons are always convex. Irregularpolygons include those where each side may have a different length, eachangle may be a different measure and are the opposite of regularpolygons. Convex is understood to mean all interior angles less than180°, and all vertices ‘point outwards’ away from the interior. Theopposite of which is concave. Regular polygons are convex. Concave isunderstood to mean one or more interior angles greater than 180°. Somevertices push ‘inwards’ towards the interior of the polygon. A polygonmay have one or more sides cross back over another side, creatingmultiple smaller polygons. It is best considered as several separatepolygons. A polygon that in not self-intersecting in this way is calleda simple polygon.

Properties of all polygons (regular and irregular) include the interiorangles at each vertex on the inside of the polygon and the angle on theoutside of a polygon between a side and the extended adjacent side. Thediagonals of a polygon are lines linking any two non-adjacent vertices.For regular polygons, there are various ways to calculate the area. Forirregular polygons there are no general formulae. Perimeter is thedistance around a polygon or the sum of its side lengths.

Properties of regular polygons include the apothem (inradius) which is aline from the center of the polygon to the midpoint of a side. This isalso the inradius—the radius of the incircle. The radius (circumradius)of a regular polygon is a line from the center to any vertex. It is alsothe radius of the circumcircle of the polygon. The incircle is thelargest circle that will fit inside a regular polygon. Circumcircle isthe circle that passes through all the vertices of a regular polygon.Its radius is the radius of the polygon.

Some embodiments herein illustrate a plurality of polygons within thematrix array. Each can impact the CT (coherence tomography). Theycontain enough pores to allow for a ‘central hexagon’. A square/diamondshape may be apparent. As a formula:

diagonal=√{square root over (s ² +s ²)} where:

-   -   s is the length of any side        which simplifies to:

diagonal=√{square root over (s)} where:

-   -   s is the length of any side

A ‘pore’ described herein may have a specific form, shape, compositionand depth. The creating of pores within a matrix array changingbiomechanical properties of connective tissue is a unique feature of thecurrent disclosure.

The ‘pore matrix’ used herein may be used to control wound healing. Insome embodiments, it may include the filling of pores to inhibit scartissue.

In some embodiments, pores may have at least 5%-95% depth through theconnective tissue, and help create the intended biomechanical propertychange. They may have a specific composition, arrangement in the matrixand desirably have the mathematical qualities of a polygon. Inthree-dimensional (3D) space the intended change in the relationshipbetween the pores in the matrix or lattice is the unique characteristicof the current disclosure (see FIGS. 1F(a) to 1F(c)). The matrix orarray can comprise of a 2D Bravais lattice, a 3D Bravais Lattice or aNon-Bravais lattice.

Referring to FIGS. 1B-1E, exemplary pore matrix arrays are illustrated.The pore matrix arrays herein are the basic building block from whichall continuous arrays can be constructed. There may be a plurality ofdifferent ways to arrange the pores on the CT in space where each pointwould have an identical “atmosphere”. That is each point would besurrounded by an identical set of points as any other point, so that allpoints would be indistinguishable from each other. The “pore matrixarray” may be differentiated by the relationship between the anglesbetween the sides of the “unit pore” and the distance between pores andthe “unit pore”. The “unit pore” is the first “pore created” and whenrepeated at regular intervals in three dimensions will produce thelattice of the matrix array seen on the surface throughout the depth ofthe tissue. The “lattice parameter” is the length between two points onthe corners of a pore. Each of the various lattice parameters isdesignated by the letters a, b, and c. If two sides are equal, such asin a tetragonal lattice, then the lengths of the two lattice parametersare designated a and c, with b omitted. The angles are designated by theGreek letters α, β, and γ, such that an angle with a specific Greekletter is not subtended by the axis with its Roman equivalent. Forexample, α is the included angle between the b and c axis.

A hexagonal lattice structure may have two angles equal to 90°, with theother angle (γ) equal to 120°. For this to happen, the two sidessurrounding the 120° angle must be equal (a=b), while the third side (c)is at 90° to the other sides and can be of any length.

Referring to FIGS. 1F(a) to 1F(c), an exemplary schematic projection ofthe basal plane of the hcp unit cell on the close packed layers isillustrated. Matrix array is defined as the particular, repeatingarrangement of pores throughout a target connective tissue, e.g., thesclera. Structure refers to the internal arrangement of pores and notthe external appearance or surface of the matrix. However, these may notbe entirely independent since the external appearance of a matrix ofpores is often related to the internal arrangement. There may be aspecific distance between each of the pores in the designated matrix tofulfill the mathematical characteristics and properties of the polygon.The pores created may also have a relationship with the remaining tissuewithin the matrix thus changing the biomechanical properties of thematrix.

Spatial relationships of the pores within the matrix may have geometricand mathematical implications.

In some embodiments, the laser microporation system (see, e.g., FIGS.3A, 3B, and 4A below) of the present disclosure generally includes atleast these parameters: 1) a laser radiation having a fluence betweenabout 1-3 μoules/cm2 and about 2 Joules/cm2; ≥15.0 J/cm² on the tissue;≥25.0 J/cm² on the tissue; to widen treatment possibilities 2900nm+/−200 nm; around the mid IR absorption maximum of water; Laserrepetition rate and pulse duration may be adjustable by usingpre-defined combinations in the range of 100-500 Hz and 50-225 μs. Thisrange may be seen as a minimum range ≥15.0 J/cm² on the tissue; ≥25.0J/cm² on the tissue; to widen treatment possibilities; 2) irradiatedusing one or more laser pulses or a series of pulses having a durationof between about 1 ns and about 20 μs. Some embodiments can potentiallyhave a up to 50 W version; 3) The range of Thermal Damage Zone (TDZ) canbe less than 20 μm in some embodiments or between 20-50 μm in someembodiments; 4) Parameters of pulse width from 10 μm-600 μm can also beincluded. (See FIG. 1E-1)

The energy per pulses 1-3 microJoules may link to femtolasers and picolasers with high rep rates, e.g., 500 Hz (Zeiss) up to several kilohertz(Optimedica). The benefit of the femtolasers and pico-lasers are thesmall spot sizes (for example, 20 microns and up to 50 microns) and theenergy densities are high for minimal thermal problems to surroundingtissues. All this can lead to an effective scleral rejuvenation. In someembodiments, the lasers may produce substantially round and conicallyshaped holes in sclera with a depth up to perforation of sclera andthermal damage from about 25 μm up to about 90 μm. The hole depth can becontrolled by the pulse energy and the number of pulses. The holediameter may vary by motion artifacts and/or defocusing. The thermaldamage may correlate with the number of pulses. The pulse energy may beincreased, which may lead to a decrease of number of pulses and withthis to a further decrease of thermal damage. The increase of pulseenergy may also reduce the irradiation time. An exemplary design of thelaser system described may allow for laser profiles optimized for lowerthermal damage zone while preserving irradiation time thus maintaining afast speed for optimal treatment time, and chart showing the correlationbetween thermal damage zone and pulse (see FIG. 1E-2 and FIGS. 1G-1 to1G-4).

The nanosecond lasers for micro poring or micro tunneling, in someembodiments, may include the following specifications: wavelengthsUV-Visible-Short infrared 350-355 nm; 520-532 nm; 1030-1064 nm typical;-pulse lengths 0.1-500 nanoseconds, passive (or active Q-switching);pulse rep. rate 10 Hz-100 kHz; peak energies 0.01-10 milliJoules; peakpowers max. over 10 Megawatts; free beam or fiber delivered.

Scleral rejuvenation can be performed with femto- or pico second lasersand Er:YAG laser. Other preferred embodiments may include laser energyparameters ideal for 2.94 Er:YAG laser or other laser possibilities withEr:YAG preferred laser energy or other lasers of different wavelengthswith high water absorption.

MilliJoules and energy densities for different spot sizes/shapes/porescan include:

Spot size 50 microns: a) 0.5 mJoules pp is equal to 25 Joules/cm2; b)1.0 mJoule pp is equal to 50 Joules/cm2 (possible with Er:YAG); 3) 2.0mJoules pp is equal to 100 Joules/cm2.

Spot size 100 microns (all these possible with Er:YAG): a) 2.0 mJoulespp is equal to 25 Joules/cm2; b) 5.0 mJoules pp is equal to 62.5Joules/cn2; c) 9.0 mJoules pp is equal to 112.5 Joules/cm2.

Spot size 200 microns: a) 2.0 mJoules pp is equal to 6.8 Joules/cm2; b)9.0 mJoules pp is equal to 28.6 Joules/cm2; c) 20.0 mJoules pp is equalto 63.7 Joules/cm2.

Spot size 300 microns: a) 9.0 mJoules pp is equal to 12.8Joules/cm2—possible with Er:YAG; b) 20.0 mJoules pp is equal to 28Joules/cm2—possible with DPM-25/30/40/X; c) 30.0 mJoules pp is equal to42.8 Joules/cm2 d) 40.0 mJoules pp is equal to 57 Joules/cm2 e) 50.0mJoules pp is equal to 71 Joules/cm2.

Spot size 400 microns: a) 20 mJoules pp is equal to 16 Joules/cm2-DPM-25/30/40/50/X; b) 30 mJoules pp is equal to 24 Joules/cm2; c) 40mJoules pp is equal to 32 Joules/cm2; d) 50 mJoules pp is equal to 40Joules/cm2

It is noted that round or square pores or spots are possible as well.

Regarding femto & picosecond lasers, some available wave lengths includeIR 1030 nm; Green 512 nm and UV 343 nm. The peak energies can vary fromnanoJoules (at MHz rep rate) via 5-50 microJoules up to several hundredmicroJoules in picosecond region. Femtosecond lasers having pulse length100-900 femtosec; peak energies from a nanoJoules to several hundredmicroJoules, pulse rep. rates from 500 Hz to several Megahertz (ZiemerLOV Z; Ziemer AG, Switzerland: nanoJoules peak energies at over 5 MHzrep. rate, beam quality/density very good-focuses in a small spot—50micron and under is possible).

The beam quality being so precise in the best femtolasers that, in someembodiments, femtolaser Micro Tunneling of sclera as micro pores usingErbium lasers can be accomplished.

As used herein, nuclear pores can be defined as openings in the nuclearenvelope, diameter about 10 nm, through which molecules (such as nuclearproteins synthesize in the cytoplasm) and ma must pass (see FIG. 1H).Pores are generated by a large protein assembly. Perforations in thenuclear membrane may allow select materials to flow in and out.

Formula for porosity in biological tissue may be defined as:X(Xa,t)=qT″(X″, t)=x*+u″(X″, t), where qT″ is a continuouslydifferentiable, invertible mapping from 0 to a, and u″ is thecY-constituent displacement. The invertible deformation gradient for thea-constituent (F″), and its Jacobian (J″) may be defined as J″=det F″,where J″ must be strictly positive to prohibit self-interpenetration ofeach continuum. The right Cauchy-Green tensor % and its inverse, thePiola deformation tensor B for the solid-constituent may be defined asV=F^(s) ^(t) F^(s), B=F^(s) ⁻¹ F^(s) ^(−t) , where the superscript tindicates transposition.

Current theoretical and experimental evidence suggests that creating ormaintaining pores in connective tissue accomplishes three importanttasks. First, it transports nutrients to the cells in the connectivetissue matrix. Second, it carries away the cell waste. Third, the tissuefluid exerts a force on the wall of the sclera or outer ocular coat, aforce that is large enough for the cells to sense. This is thought to bethe basic mechanotransduction mechanism in the connective tissue, theway in which the ocular coat senses the mechanical load to which it issubjected and the response to the increase in intraocular pressure.Understanding ocular mechanotransduction is fundamental to theunderstanding of how to treat ocular hypertension, glaucoma and myopia,

Deriving the physical properties of a porous medium (e.g., hydraulicconductivity, thermal conductivity, water retention curve) fromparameters describing the structure of the medium (e.g., porosity, poresize distribution, specific surface area) is an ongoing challenge forscientists, whether in soft tissues or for porosities of bone tissue andtheir permeabilities. To verify the assumption of a porous medium havinga self-similar scaling behavior, fractal dimensions of various featureshave been determined experimentally.

System Procedure and Mechanism of Action

While some current accommodative theory states that the lens isprimarily responsible for the refractive change allowing us to read, allelements of the zonular apparatus have been found to be involved.Illumination of the role that extralenticular processes play inaccommodation support the theory that scleral therapies, which modifybiomechanical properties by restoring compliance to an otherwise rigidtissue, may influence accommodative ability in presbyopes.

Recent studies have found that presbyopia may not be a refractive erroror simply the loss in the ability to focus on near objects. Instead, itis the age-related consequences on connective tissues of the eye organor oculus, just as they occur throughout the body. This produces asignificant but reversible impact on the biomechanical efficiencies ofocular functions, specifically accommodation, which potentially improvesnot only dynamic visual focusing capability but also ocularbiotransport, and ocular metabolic efficiency. These studies are basedon the fundamental and natural biological occurrences that occur withage, and specifically resonates on the effects of ocular rigidity to theaccommodative structures beneath the major outer coat of the eye orsclera. The sclera undergoes a gradual “sclerosclerosis” with age, whichrepresents the normal and gradual irreversible changes which occur inall connective tissues. This sclerotic process increases scleralcompression, which imposes staggeringly significant load, stress, andstrain upon underlying and related ocular and intraocular structures.This ocular rigidity or stress and strain upon the ciliary body andrelated structures which control dynamic accommodation, impact thebiomechanics of the eye and compromises the eye's ability to perform itscore organ functions.

In some embodiments, an ocular laser surgery and therapeutic treatmentssystem may provide an eye laser therapy procedure designed to alleviatethe stresses and strain that occur with an increasingly rigid sclerawith age by creating compliance in the scleral tissue using a lasergenerated matrix of micropores in the scleral tissue. The system mayfacilitate biomechanical property changes in the sclera, alleviatecompression of the subliminal connective tissue, facial tissue, andbiophysiological structures of the eye, and restore accommodativeability. The system may alleviate stress and increase biomechanicalcompliance over the ciliary muscle, the accommodation complex, and keyphysiological anatomy that lies directly beneath the aging scleraltissue.

In some embodiments, the laser therapy procedure of the presentdisclosure may target specific treatment areas which are in distinctphysiological zones covering critical anatomy inside the eye relative toeye function. Although examples of 3 or 5 physiological zones aredescribed herein, other number of physiological zones may also beconsidered for treatments.

In some embodiments, a treatment pattern may be described as 3 criticalzones in 3 distinct distances from the outer edge of the anatomicallimbus (AL), not touching any components or relative tissues of thecornea. These zones are illustrated in FIGS. 2A-1 to 2A-2. In someembodiments, a treatment pattern may be described as 5 critical zones in5 distinct distances from the outer edge of the anatomical limbus (AL),not touching any components or relative tissues of the cornea, asillustrated in FIGS. 2B-1 to 2B-3.

The laser therapy procedure may use an erbium: yttrium-aluminum-garnet(Er:YAG) laser to create microspores in the sclera. These micropores maybe created at a plurality of depths with preferred depth range, e.g.,from 5%-95% of the sclera, up to the point where the blue hue of thechoroid is just visible. The micropores may be created in a plurality ofarrays including a matrix array, e.g., 5 mm×5 mm, 7 mm×7 mm, or 14 mm×14mm matrix array. These microporation matrices break bonds in the scleralfibrils and microfibrils having an ‘uncrosslinking’ effect in thescleral tissue. A direct consequence of this matrix pattern may be thecreation of areas of both positive stiffness (remaining interstitialtissue) and negative stiffness (removed tissue or micropores) in therigid sclera. These areas of differential stiffness allow theviscoelastic modulus of the treated sclera to be more compliant over thecritical zones when subjected to force or stress, such as contraction ofthe ciliary muscles. Additionally, the treated regions of the sclera mayproduce a dampening effect in rigid scleral tissue when the ciliarymuscles contract, due to increased plasticity. This enhancesaccommodative effort by directing unresisted forces inward andcentripetally toward the lens or facilitating inward upward movement ofthe accommodative mechanism. This is an advantage over models thatpostulate a net outward-directed force at the lens equator. For example,techniques which are directed at scleral expansion such as scleralimplants or surgical laser radial ablations such as LAPR are alldirected at increasing ‘space’ or circumlental space to allow the sclerato expand for the intention of giving the ciliary muscle room. Thesetechniques are based on the ‘lens crowding’ theory and aim to induce theoutward movement rather than the upward and inward movement of thesclera and ciliary mechanism. Overall, the creation of the microporematrices in the scleral tissue may induce an ‘uncrosslinking effect’,severing the fibrils and microfibrils of the layers of the scleraallowing a more compliant response to applied stress. Thus, the proposedmechanism of action for the system of the present disclosure is toincrease plasticity and compliance of scleral tissue over critical zonesof anatomical significance by creating these regions of differentialstiffness over the ciliary complex, and thereby improve biomechanicalfunction and efficiency of the accommodation apparatus. FIGS. 2C-1 to2C-4 illustrate in some embodiments laser scleral uncrosslinking ofscleral fibrils and microfibrils.

Referring to FIGS. 2D-1 to 2D-4, using a novel model, the effect of theprocedure on ocular rigidity has been investigated. Ocular connectivetissues are impacted, like all other connective tissues, by age. Thesclera constitutes 5/6 of the oculus and is made up of dense irregularconnective tissue. It is comprised primarily of collagen (50-75%),elastin (2-5%), and proteoglycans. The connective tissues of the eyestiffen with increasing age losing their elasticity largely due to thecrosslinking that occurs with age. Crosslinking creates an “increase inbiomechanical stiffness” in connective tissues such as those in the eye.Crosslinks are bonds between polymer chains, such as those in syntheticbiomaterials or the proteins in connective tissues. Crosslinking can becaused by free radicals, ultraviolet light exposure, and aging. Inconnective tissues, collagen and elastin can crosslink to continuouslyform fibrils and microfibrils over time. With increasing amounts offibrils and microfibrils, the sclera stiffens, undergoing a‘sclerosclerosis’, as well as a concomitant increase in metabolicphysiological stress. As this pathophysiology progresses, the scleraexerts compression and loading stresses on underlying structures,creating biomechanical dysfunction, specifically those related toaccommodation. Laser scleral microporation breaks scleral fibrils andmicrofibrils effectively “uncrosslinking” bonds thereby increasingscleral compliance and “decreasing biomechanical stiffness”.

In some exemplary operations, six freshly harvested porcine eyes weremodified by crosslinking (0.8 ml of 2% glutaraldehyde for 10 minutes) tomimic the ocular rigidity of an older human eye (e.g., 60 years), basedon the ocular rigidity coefficient model of Pallikaris et al. Sevenfreshly harvested porcine eyes were left unmodified to mimic the ocularrigidity of a young human eye (e.g., 30 years). Three of the eyes ineach group received the treatment, while the remaining eyes were used ascontrols. In brief, the investigation used a pressure transducer (up to5 psi), a dosage injector controller, a data computerized reader, andtissue holding frame to which each porcine eye was fixed, to generate anintraocular pressure (IOP) versus injected volume curve for each eye.The ocular rigidity coefficient (K=d ln(P)/dV [in mmHg/μl]) was thencalculated as the slope of ln(IOP) (from IOP between 30-50 mmHg) versusinjected volume. In the young eye, the treatment resulted in a 10.8%decrease in rigidity. In the older eye, the treatment resulted in a30.1% decrease in rigidity. Using an analysis of variance (e.g., ANOVA)and Tukey honestly significant difference (TukeyHSD) test, theinvestigation found that the system of the present disclosuresignificantly reduced ocular rigidity in the old eyes and overall(p=0.0009; p=0.0004). This decrease in ocular rigidity may be caused by‘uncrosslinking’ aging tissue.

In some exemplary operations, twenty-six subjects underwent thetreatment, and 21 completed 24 months of post-operative care. Fivepatients withdrew, due to occupational travel conflicts. Thepre-operative (month 0) and post-operative IOP (determined by pneumatictonometry) data were kept. There is an immediate 5% drop in IOP for thepatient eyes compared to pre-operative IOP. Over the two years followingthe treatment, patient IOP remains approximately 15% lower thanpre-operative IOP. The immediate and sustained reduction in IOP could bedemonstrative of an improvement in aqueous outflow following thetreatment. Using an ANOVA and TukeyHSD test, these differences werestatistically significant beginning at post-operative month 3 andcontinued through all subsequent months (p=0.000063 at 24 monthspostoperatively). This reduction in IOP may be indicative of enhancedocular mobility and a decrease in ocular rigidity following thetreatment.

The biomechanical improvements with the treatment may prove to increasethe biomechanical efficiency of the accommodative apparatus. In someembodiments, by creating micropores in a matrix over four obliquequadrants, the treatment may restore functional extralenticular forces,and restore a minimum of 1-3 diopters of accommodation. Treatments usingthe system and methods of the present disclosure may show an average of1.5 diopters of accommodation post-operatively. This significantlyimproved the visual acuity of our patients. Visual acuity was measuredusing standard Early Treatment Diabetic Retinopathy Study (ETDRS)charts, and statistical analysis was done using an ANOVA and TukeyHSDtest. The uncorrected monocular near visual acuity of the patients was0.25±0.18 log MAR (mean±standard deviation) at 24 monthspost-operatively, compared to 0.36±0.20 log MAR (mean±standarddeviation) pre-operatively (p<0.00005).

Utilizing innovative biometry and imaging technologies that were notpreviously available has illuminated that the loss of accommodativeability in presbyopes has many contributing lenticular, as well asextralenticular and physiological factors. The lens, lens capsule,choroid, vitreous, sclera, ciliary muscles, and zonules all play acritical role in accommodation, and are affected by increasing age.Increasing ocular rigidity with age produces stress and strain on theseocular structures and can affect accommodative ability.

Scleral therapies may have an important role in treating biomechanicaldeficiencies in presbyopes, by providing at least one means to addressthe true etiology of the clinical manifestation of the loss ofaccommodation seen with age. The treatment, utilizing lasermicroporation of the sclera to restore more pliable biomechanicalproperties, is a safe procedure, and can restore accommodative abilityin aging adults. As a result, the treatment may improve dynamicaccommodative range as well as aqueous outflow. With the advent ofimproved biometry, imaging, and research focus, information about howthe accommodation complex works and how it impacts the entire eye organcan be achieved.

Referring to FIG. 2(a), exemplary three critical zones of significanceas measured from the anatomical limbus (AL)) are shown. Zone 1) 0.5-1.1mm from the AL, over the scleral spur at the origin of the ciliarymuscle; Zone 2) 1.1-4.9 mm from the AL, over the mid ciliary musclebody; Zone 3) 4.9-5.5 mm from the AL, over the insertion of thelongitudinal muscle fibers of the ciliary, just anterior to the oraserrata at the insertion of the posterior vitreous zonules. FIG. 2E(b)illustrates exemplary restored mechanical efficiency and improvedbiomechanical mobility.

In some embodiments, the laser scleral microporation procedure mayinvolve using the laser described above to perform partial-thicknessmicro-ablations in the sclera in a matrix in five critical anatomiczones, for example, 0-7.2 mm from the anatomical limbus (AL). In someembodiments, the five zones may include: Zone 0) 0.0-1.3 mm from AL;distance from the AL to the superior boundary of ciliary muscle/scleralspur; Zone 1) 1.3-2.8 mm from AL; distance from the sclera spur to theinferior boundary of the circular muscle; Zone 2) 2.8-4.6 mm from AL;distance from the inferior boundary of the circular muscle to theinferior boundary of the radial muscle; Zone 3) 4.6-6.5 mm from AL;inferior boundary of the radial muscle to the superior boundary of theposterior vitreous zonule zone; and Zone 4) 6.5-7.2 mm from AL; superiorboundary of the posterior vitreous zonule zone to the superior boundaryof the ora serrata.

FIG. 2F illustrates an exemplary matrix array of micro-excisions, usingthe systems and methods of the present disclosure, in four obliquequadrants.

FIG. 2G illustrates an exemplary graphical representation of restoredocular compliance, decreased scleral resistive forces, increased ciliaryresultant forces, and restored dynamic accommodation following thetreatment.

FIG. 2H illustrates an exemplary box-and-whiskers plot of the ocularrigidity for control (black) and treated (grey) porcine eyes. The upperand lower extremities of the box represent the 75th and 25thpercentiles, the bar within the box represents the median, and thewhiskers represent the full extent of the data ranges.

FIG. 2I illustrates an exemplary box-and-whiskers plot of pre- andpost-operative intraocular pressure (IOP) for the patient eyes. Thestars indicate a significant difference from pre-operative IOP. Theupper and lower extremities of the box represent the 75th and 25thpercentiles, the bar within the box represents the median, the whiskersrepresent the full extent of the data ranges, and the white circlesrepresent outliers.

FIG. 2J illustrates exemplary charts showing uncorrected anddistance-corrected visual acuity at distance 4 m, intermediate (60 cm),and near (40 cm) for a) monocular and b) binocular patient eyes. Errorbars represent mean±SD.

As described herein, accommodation of a human eye may occur through achange or deformation of the ocular lens when the eye transitions fromdistant focus to near focus. This lens change may be caused bycontraction of intraocular ciliary muscles (ciliary body), whichrelieves tension on the lens through suspensory zonule fibers and allowsthe thickness and surface curvature of the lens to increase. The ciliarymuscle can have a ring-shaped and can be composed of three uniquelyoriented ciliary fiber groups that contract toward the center andanterior of the eye. These three ciliary fiber groups are known aslongitudinal, radial and circular. Deformation of the ciliary muscle dueto the contraction of the different muscle fibers translates into orotherwise causes a change in tension to the surface of the ocular lensthrough zonule fibers, whose complex patterns of attachment to the lensand ciliary muscle dictate the resultant changes in the lens duringaccommodation. Ciliary muscle contraction also applies biomechanicalstrain at the connection locations between the ciliary muscle and theocular sclera, known as the white outer coat of the eye. Additionally,biomechanical compression, strain or stress can be caused duringaccommodation can occur at connection locations between the ciliarymuscle and the choroid, known as the inner connective tissue layerbetween the sclera and ocular retina. Ciliary muscle contraction canalso cause biomechanical forces on the trabecular meshwork, laminacribrosa, retina, optic nerve and virtually every structure in the eye.

In some embodiments, applying the techniques and models described withrespect to the various embodiments herein using simulations can lead tooutputs and results that fall within known ranges of accommodation of ayoung adult human.

3D mathematical models can incorporate mathematics and non-linearNeohookean properties to recreate behavior of the structures ofbiomechanical, physiological, optical and clinical importance.Additionally, 3D (Finite Element Model) FEM models can incorporate datafrom imaging, literature and software relating to the human eye.

Visualization of accommodation structures during and after simulationsmay be included in addition to means for measuring, evaluating andpredicting Central Optical Power (COP). These can be used to simulateand view age specific whole eye structures, optics, functions andbiomechanics. Further, they can independently simulate properties of theciliary muscle, extra-lenticular and lenticular movements of the ocularlens and functions on the ocular lens. Individual simulations ofanatomical structures and fibers can reveal biomechanical relationshipswhich would otherwise be unknown and undefined. Numerical simulation ofthe patient's eye can be created using 3D FEM meshing to accomplishthese operations.

To elaborate, representative 3D geometry of resting ocular structurescan be computationally defined based on extensive review of literaturemeasurements and medical images of the anatomy of young adult eyes andthrough modeling. Specialized methods implemented in software, such asAMPS software (AMPS Technologies, Pittsburgh, Pa.), can be used toperform geometric meshing, material property and boundary conditionsdefinitions, and finite element analysis during the modeling stage.Ciliary muscle and zonules can be represented as a transverse isotropicmaterial with orientations specified to represent complex fiberdirections. Additionally, computational fluid dynamic simulations can beperformed in order to produce fiber trajectories, which can then bemapped to the geometric model.

Initially, a lens modeling can include a lens in a relaxedconfiguration, before being stretched by pre-tensioning zonule fibers toan unaccommodated position and shape. Unaccommodated lens position canbe reached when zonules are shortened, e.g., to between 75% and 80% oftheir starting length, and more particularly to about 77% of theirstarting length. Then accommodative motion can be simulated byperforming active contraction of the various fibers of the ciliarymuscle. In some embodiments, this can be accomplished using previousmodels of skeletal muscle that are modified to represent dynamicsparticular or otherwise specific or unique to the ciliary muscle. Modelresults representing lens and ciliary anterior movement and deformedocular lens thickness at a midline and apex can be validated orotherwise verified by comparing them to existing medical literaturemeasurements for accommodation. In order to investigate contributions ofthe various ciliary fiber groups to the overall action of the ciliarymuscle, simulations can be performed for each fiber group by activatingeach in isolation while others remain passive or otherwise unchanged.

Various beneficial aspects of the embodiments described below aredescribed with respect to simulations applying pre-tensioning zonulesmodels and contracting ciliary muscle models.

With respect to the pre-tensioning zonules, modeling can include: 1)Creation of 3D material sheets oriented between measured zonularattachment points of insertion on the lens and origination on theciliary/choroid; 2) specified fiber direction in the plane of the sheet(e.g., fibers directed from origin to insertion); and 3) Transverselyisotropic constitutive material with tension development in thepreferred direction. Further, with particular respect to 3), advantageshave been achieved, including: a) Time-varying tension parameter inputregulates the stress developed in the material; b) Time-varying tensioninput may be tuned to produce required strain in the lens to matchmeasurements of the unaccommodated configuration; c) Age variation inmaterial properties and geometries to produce age-related impact; and d)others.

With respect to the contracting ciliary muscle models, modeling caninclude: 1) Modified constitutive model to represent smooth and skeletalaspects of ciliary mechanical response; 2) a plurality of, e.g., 3, setsof specified fiber directions to represent physiological orientation ofmuscle cells and lines of action of force production; and 3)Transversely isotropic constitutive material with active forcedevelopment in the preferred direction. Further, with particular respectto 3) advantages have been achieved, including: a) Activation parameterinput regulates the active stress developed in the material; b)Activation input may be tuned to produce appropriate accommodativeresponse to match literature measurements; c) Activation of individualmuscle fiber groups can be varied in isolation to assess contributionsto lens strain/stress; d) Activation of individual muscle fiber groupscan be varied in isolation to assess contributions to ocular scleralstrain/stress; e) Activation of individual muscle fiber groups can bevaried in isolation to assess contributions to choroidal strain/stress;and f) others.

In various embodiments, simulation results can be governed bymodification of tensioning and activation inputs to the zonule andciliary materials, as opposed to performing an applied displacement toexternal node(s) of a mesh.

Thereafter, systems, methods and devices for providing a predictiveoutcome in the form of a 3D Computer Model with integrated ArtificialIntelligence (AI) can be used to find predictive best instructions for atherapeutic ophthalmic correction, manipulation, or rehabilitation of apatient's vision defects, eye disease, or age-related dysfunction aredisclosed. The predictive best instruction can be derived from physicalstructural inputs, neural network simulations, and prospectivetherapeutic-outcome-influencing. New information can be analyzed inconjunction with optimized, historical therapeutic-outcome informationin order to provide various benefits. The concepts herein can be used toperform a multitude of simulations and include a knowledge-basedplatform so that the system may be able to improve its instructionresponse as the database is expanded.

In some embodiments, the stored instructions contemplated can preferablybe an optimized, custom, photoablative algorithm for driving aphotoablative, photothermal laser. The instructions can be providedalong with an AI processor via direct integration, stand-aloneimportation or remotely, e.g., via a Bluetooth or other wireless enabledapplication or connection. These instructions can be performed a priorior intraoperatively.

In some embodiments, the stored instructions contemplated can preferablybe an optimized custom ocular lens simulation algorithm used forsimulating manipulation of an implantable intraocular lens in order toimprove medical procedures and understanding.

The instructions can also be set up as a ‘stand-alone’ system, wherebythe instructions can be provided with independent research design inputsand outputs to test various conditions and responses of the eye tosurgical manipulations, implantation devices, or other therapeuticmanipulations of the eye, in order to optimize design and outcomeresponse.

Additionally, these instructions can also include one or more of: analgorithm for image processing interpretation, expansion of ophthalmicimaging data platforms and a companion diagnostic to an imaging device.

As described herein, methods for improving ophthalmic treatments,surgeries, or pharmacological interventions can include obtainingtopological, topographical, structural, physiological, morphological,biomechanical, material property, and optical data for a human eye alongwith applied physics and analyzing through mathematical simulationsusing artificial intelligence networks.

In some embodiments, applications using simulation can includetechniques executed via devices, systems and methods for automateddesign of an ophthalmic surgical procedure including physicalmeasurements and applied physics of a patient's whole eye are obtained.Techniques known in the art can be used to obtain these measurements.The information measured can be interpolated and extrapolated to fitnodes of a finite element model (FEM) of a human eye for analysis, whichcan then be analyzed to predict an initial state of stress of the eyeand obtain pre-operative conditions of the cornea, lens and otherstructures. Incision data constituting an “initial” surgical plan can beincorporated into the finite element analysis model. A new analysis canthen be performed to simulate resulting deformations, biomechanicaleffects, stresses, strains, curvatures of the eye as well as dynamicmovements of the eye, more specifically the ciliary muscles, lens andaccommodative structures. These can be compared to original valuesthereof and to a vision objective. If necessary, a surgical plan can bemodified and resulting new ablation data can be entered into the FEM andthe analysis is repeated. This procedure can be repeated as desired ornecessary until the vision objectives are met.

In some embodiments, Artificial Intelligence (AI) software can use alearning machine, e.g., an artificial neural network, to conduct machinelearning, whereby the system can learn from the data, and therefore hasa learning component based on the ongoing database expansion. It can beoperative to improve reliability as the database is formulated andupdated, heretofore unknown in the prior art of 3D predictive modelingsystems, methods and devices.

Simulation can include Age Progression simulation of a patient's eye,having a predictive capacity to simulate ophthalmic surgical outcomes,determine rates of regression of treatments, as well as executepredictive algorithms for future surgical or therapeutic enhancement,heretofore unknown in the prior art of 3D predictive modeling systems,methods and devices.

In some embodiments, the systems of the present disclosure may include avirtual eye simulation analyzer that can include integration ofinformation related to all structures of an eye into a computer programfor the purpose of simulating biomechanical and optical functioning ofthe eye, as well as age related simulations for clinical applicationpurposes.

The virtual eye simulation analyzer systems, devices and methods caninclude an output display that can be viewed by users as a standalone orintegrated display system, along with other equipment.

Information used as inputs for the simulator can include imaginginformation for Biometry (UBM, OCT and others). Dynamic Imaging can beperformed using UBM, OCT and others. Anatomy information can includegeometry, histology and others. Physiological function information caninclude dynamic accommodation, aqueous flow, intraocular pressures,pulsatile ocular blood flow, retinal performance or compromise andothers. Material Properties of tissues of the eye, physics andbiomechanical information related to relative biomechanics can also beused.

The simulator can incorporate mathematics and non-linear Neohookeanproperties in order to recreate behavior of the structures ofbiomechanical, physiological, optical and others that may be valuable orotherwise of clinical importance. The simulator can use methods known inthe art to input data incorporated into a 3D FEM with a patient's uniquedata based on analysis of their own individual eye or eyes. Further, thesimulator can use methods known in the art to input data and create anumerical simulation of the patient's eye using a 3D FEMmeshing—essentially creating a custom dynamic real-time “Virtual Eye,”heretofore unknown in the prior art of 3D predictive modeling systems,methods and devices.

In some embodiments, the AI may be capable of learning via predictivesimulation and can be operative to improve simulative predictions forsurgical or therapeutic manipulations of the eye through learningmachine, such as artificial neural networks, e.g., in an “ABACUS”program. Such program can also be capable of providing instructionsdirectly to a communicatively coupled processor or processing system tocreate and apply algorithms, mathematical sequencing, formulageneration, data profiling, surgical selection and others. It can alsobe capable of providing instructions directly to a workstation, an imageprocessing system, a robotic controller or other device forimplementation. Further, it can be capable of providing instructionsindirectly through a Bluetooth or other remote connection to a roboticcontroller, an image system or other workstation.

The models herein can have various applications for clinical, researchand surgical use, including: 1) use of prior evaluation and simulationof accommodation functions of the eye (examples including Presbyopiaindication-IOL design and use, extra-lenticular therapeutics and theiruses); 2) use of prior evaluation and simulation of aqueous flow of theeye, such as for glaucoma indications; 3) virtual simulations and realtime simulations of efficacy of IOL's, therapeutic treatments andvarious biomechanical implications; 4) virtual simulations using the AIand CI to reproduce customized aging effects on an individual'sbiomechanical and physiological functions of their eye which haveclinical importance; 5) Surgical Planning; 6) design model (such as FEM)importation and simulation, such as for IOL's and others; 7) Virtualclinical trials and analysis; 8) real-time intraoperative surgicalanalysis, planning and execution; 9) Performance of a crystalline lensof the eye as it relates to optical and biomechanical dysfunction,cataract formation and the like; and 10) others.

Additional components of simulators may include: 1) Eye Scanning; 2)Optical inputs such as a) Cornea optics, wavefronts, elastography,hysteresis, visual acuity topography, connective tissue macro and microstructure and b) lens optics such as wavefront, visual acuity,topography, lens opacity, light scatter, central optical power (COP)during accommodation and disaccommodation, elastography, viscoelasticproperties and others; 3) Scleral biomechanics, viscoelastic, materialproperties, stress, strain mapping, connective tissue macro/microstructure; 4) Trabecular meshwork material, viscoelastic, connectivetissue macro and micro structure; 5) Lamina cribrosa materialproperties, stress, strain viscoelastic, connective tissue macro andmicrostructure; 6) Physiological Inputs including a) Aqueous outflow andinflow, b) Intra Ocular Pressure (IOP), c) Ocular pulsatile blood flow,d) Retinal activity and others; 7) Surface Spectroscopy; 8) CollagenFibril characterization of the cornea, sclera, lens, and others; and 9)others.

Benefits of simulators in an accommodation embodiment may include: 1)Measuring, analyzing and simulating accommodation of an eye inreal-time; 2) Demonstrating accommodation biomechanics in real-time; 3)Evaluating accommodation biomechanics; 4) Visualization of accommodationstructures; 5) Measuring, evaluating and predicting Central OpticalPower; 6) Simulating age progression of whole eye structures, functionsand biomechanics; and 7) others.

Major structural component inputs can be based on the sclera, cornea,lens, trabecular meshwork, lamina cribrosa, retina and others. For thesclera, these can include: Scleral rigidity, viscoelasticity, Scleralthickness, Scleral depth, 3D surface topology, top surface spectraldimensions, 3D spectroscopy and others. For the cornea, these caninclude: Corneal Wavefront, viscoelasticity, Topography, Keratotomy,Corneal thickness, 3D topology, K readings, Corneal stiffness, 3Dspectroscopy and others. For the lens, these can include: LenticularWavefront, Central optical power, Accommodative amplitude, Lightscattering, Opacity and others. For the trabecular meshwork, these caninclude: elasticity, outflow, inflow and others. For the lamina cribrosathis can include: porosity, mechanical dependence, perfusion,poroelasticity, cup floor depth, and others.

Some of the various major optical profiles, properties, information andvisual acuity information outputs for a cornea can include: Totalaberrations, Visual Strehl Ratio, Depth of focus, MRSE, Visual acuity,lens scatter and others. Some of the various major optical profiles,properties, information and visual acuity information outputs for a lenscan include: Total aberrations, VSOF, Depth of focus and others.

Described herein are example embodiments of a creation of a 3DMicroporation Model on a spherical surface, and example embodiments ofPantec Protocols Revised Fibonacci MatLab Pore Calculation for Whole EyePatterns.

Referring to FIG. 2K-1, an example of Protocol Execution is nowdescribed: Protocol 1.1: 225 μm (169 Total Pores @ 3%=42.25Pores/Quadrant). An example of Matlab code used for Protocol 1.1 mayinclude: >>fibonacci_spiral_connected (‘r’,0.225,3,6.62,9.78). Matlabcode parameter breakdown may include: Parameter 1, ‘r’=pore shape: typein ‘r’ for rectangular or ‘c’ for circular pore shape. [[.]] Use ‘r’ for‘please’ and ‘c’ for ‘DPM25’*; Parameter 2, 225 μm (0.225)=r_shape:length of the rectangular pore shape or the radius of the circular poreshape in [mm]; Parameter 3, 3%=D: pore density in [percent]; Parameter4, 6.62 mm (Radius of the zone taken away from the pore calculation).This is so there is no pore calculated in the corneal/limbus area (6.62mm)=r_b: radius for the beginning of the circle in [mm]; Parameter 5,9.78 mm (Radius to the end of the zone for pore calculation). The 6.62mm radius will be subtracted from the process of the pore calculation,thus allowing 6.62 mm to 9.78 mm radius being the only calculated areawith pores=r_e: radius for the ending of the circle in [mm]. Once thecode ((‘r’,0.225,3,6.62,9.78)) is entered in Matlab, it will output thefigure generated specifically for this pore protocol. It is how theexemplary title got its total pore number.

Therapy Manipulation protocols: The following are exemplary protocolsfor Therapy Manipulation, which may be 2 Manipulations per Protocol: a)First Manipulation of entire quadrant area; b) Second Manipulation of“Patch” area 5×5 mm diamond, i) A diamond having a length of itsdiagonal=5*√{square root over ((2))}=7.07 mm, ii) A 5×5 matrix to placeon the sphere we have updated so the Fibonacci spirals can meet models.

Sphere comparison: the “Patch” is 5×5 in some embodiments Er:YAG laserwith fiber optic probe; 600 μm spot size; Nine micro-excisions in the 4oblique quadrants; 10 min/eye treatment time; Micropores in the criticalzones (e.g., 3 or 5 zones) over the ciliary complex; Creation of pliablematrix zones in the sclera.

Procedure Objectives can include: 1) Improve compliance of sclera overciliary muscle complex critical anatomy; 2) Restore mechanicalefficiency of the natural accommodative mechanism; 3) Improvebiomechanical mobility to achieve accommodative power; and others.

In some exemplary operations, an exemplary Fibonacci treatment patternwas generated through Matlab or other programs in two dimensions. Whenhaving correctly sized patches, such as 5×5 mm, it may make an actualtreatment that may not fit in the critical zones (e.g., zones 1-3, or1-5). There is a way to get an actual estimate from a 3D model to a 2Dmodel. As illustrated in FIG. 2K-1, exemplary parameters can include:

Baseline: 600 μm (92 Total Pores @ 16%=23 Pores/Quadrant).

Spot Size: 600 μm; Depth: 80%; Density: 16%; Volume Removed: 1.16 mm³;Total Pores Entirety: 92; Total Pores/Quadrant: 23.

Protocol 1.1: 225 μm (169 Total Pores @ 3%=42.25 Pores/5.5 mm Patch:Validated) Total Pores/5.5 mm patch.

FIGS. 2K-1-A to 2K-1-C illustrate exemplary protocol parametersproducing a diamond pattern for 3 critical zones.

In some embodiments, it can be important to know what is in eachprotocol how many pores are in the 5×5 patch on the 3D model pursuant tothe changing density and the changing spot size. Once known, patchmanipulations can be performed.

FIGS. 2K-2 to 2K-17 illustrate exemplary embodiments of microporationpatterns of a plurality of micropores with a plurality of densities anda plurality of spot sizes, with their various exemplary protocols used.These protocols include:

Protocol 1.1: 225 μm (96 Total Pores @ 3%=24 Pores/Quadrant: Validated)

Spot Size: 225 μm; Depth: 80%; Density: 3%; Volume Removed: 0.91 mm³;Total Pores Entirety: 96; Total Pores/Quadrant: 24

Protocol 1.2: 225 μm (161 Total Pores @ 5%=40.25 Pores/Quadrant:Validated)

Spot Size: 225 μm; Depth: 80%; Density: 5%; Volume Removed: 1.52 mm³;Total Pores Entirety: 161; Total Pores/Quadrant: 40.25

Protocol 1.3: 225 μm (257 Total Pores @ 8%=64.25 Pores/Quadrant:Validated)

Spot Size: 225 μm; Depth: 80%; Density: 8%; Volume Removed: 2.43 mm³;Total Pores Entirety: 257; Total Pores/Quadrant: 64.25

Protocol 1.4: 250 μm (565 Total Pores @ 10%=141.25 Pores/Quadrant:Validated)

Spot Size: 250 μm; Depth: 80%; Density: 10%; Volume Removed: 3.04 mm³;Total Pores Entirety: 565; Total Pores/Quadrant: 141.25

Protocol 2.1: 250 μm (100 Total Pores @ 3%=25 Pores/Quadrant: Validated)

Spot Size: 250 μm; Depth: 80%; Density: 3%; Volume Removed: 0.91 mm³;Total Pores Entirety: 100; Total Pores/Quadrant: 25

Protocol 2.2: 250 μm (166 Total Pores @ 5%=41.5 Pores/Quadrant:Validated)

Spot Size: 250 μm; Depth: 80% Density: 5%; Volume Removed: 1.52 mm³;Total Pores Entirety: 166; Total Pores/Quadrant: 41.5

Protocol 2.3: 250 μm (265 Total Pores @ 8%=66.25 Pores/Quadrant:Validated)

Spot Size: 250 μm; Depth: 80%; Density: 8%; Volume Removed: 2.43 mm³;Total Pores Entirety: 265; Total Pores/Quadrant: 66.25

Protocol 2.4: 250 μm (332 Total Pores @ 10%=83 Pores/Quadrant:Validated)

Spot Size: 250 μm; Depth: 80%; Density: 10%; Volume Removed: 3.04 mm³;Total Pores Entirety: 332; Total Pores/Quadrant: 83

Protocol 3.1: 325 μm (59 Total Pores @ 3%=14.75 Pores/Quadrant:Validated)

Spot Size: 325 μm; Depth: 80%; Density: 3%; Volume Removed: 0.91 mm³;Total Pores Entirety: 59; Total Pores/Quadrant: 14.75

Protocol 3.2: 325 μm (98 Total Pores @ 5%=24.5 Pores/Quadrant:Validated)

Spot Size: 325 μm; Depth: 80%; Density: 5%; Volume Removed: 1.52 mm³;Total Pores Entirety: 98; Total Pores/Quadrant: 24.5

Protocol 3.3: 325 μm (157 Total Pores @ 8%=39.25 Pores/Quadrant:Validated)

Spot Size: 325 μm; Depth: 80%; Density: 8%; Volume Removed: 2.43 mm³;Total Pores Entirety: 157; Total Pores/Quadrant: 39.25

Protocol 3.4: 325 μm (196 Total Pores @ 10%=49 Pores/Quadrant:Validated)

Spot Size: 325 μm; Depth: 80%; Density: 10%; Volume Removed: 3.04 mm³;Total Pores Entirety: 196; Total Pores/Quadrant: 49

Protocol 4.1: 425 μm (34 Total Pores @ 3%=8.5 Pores/Quadrant: Validated)

Spot Size: 425 μm; Depth: 80%; Density: 3%; Volume Removed: 0.91 mm³;Total Pores Entirety: 34; Total Pores/Quadrant: 8.5;

Protocol 4.2: 425 μm (57 Total Pores @ 5%=14.25 Pores/Quadrant:Validated)

Spot Size: 425 μm; Depth: 80%; Density: 5%; Volume Removed: 1.52 mm³;Total Pores Entirety: 57; Total Pores/Quadrant: 14.25

Protocol 4.3: 425 μm (92 Total Pores @ 8%=23 Pores/Quadrant: Validated)

Spot Size: 425 μm; Depth: 80%; Density: 8%; Volume Removed: 2.43 mm³;Total Pores Entirety: 92; Total Pores/Quadrant: 23

Protocol 4.4: 425 μm (115 Total Pores @ 10%=28.75 Pores/Quadrant:Validated)

Spot Size: 425 μm; Depth: 80%; Density: 10%; Volume Removed: 3.04 mm³;Total Pores Entirety: 115; Total Pores/Quadrant: 28.75

Below are exemplary code references for the protocols:

fibonacci_spiral_connected (‘r’,0.225,3,6.62,9.78)>>1.1

fibonacci_spiral_connected (‘r’,0.225,5,6.62,9.78)>>1.2

fibonacci_spiral_connected (‘r’,0.225,8,6.62,9.78)>>1.3

fibonacci_spiral_connected (‘r’,0.225,10,6.62,9.78)>>1.4

fibonacci_spiral_connected (‘c’,0.125,3,6.62,9.78)>>2.1

fibonacci_spiral_connected (‘c’,0.125,5,6.62,9.78)>>2.2

fibonacci_spiral_connected (‘c’,0.125,8,6.62,9.78)>>2.3

fibonacci_spiral_connected (‘c’,0.125, 10,6.62,9.78)>>2.4

fibonacci_spiral_connected (‘c’,0.1625,3,6.62,9.78)>>3.1

fibonacci_spiral_connected (‘c’,0.1625,5,6.62,9.78)>>3.2

fibonacci_spiral_connected (‘c’,0.1625,8,6.62,9.78)>>3.3

fibonacci_spiral_connected (‘c’,0.1625,10,6.62,9.78)>>3.4

fibonacci_spiral_connected (‘c’,0.2125,3,6.62,9.78)>>4.1

fibonacci_spiral_connected (‘c’,0.2125,5,6.62,9.78)>>4.2

fibonacci_spiral_connected (‘c’,0.2125,8,6.62,9.78)>>4.3

fibonacci_spiral_connected (‘c’,0.2125,10,6.62,9.78)>>4.4

As noted, the inputs may include: Pore Diameter (μm); Pore Depth (μm); #of Pores; Density of Pores; Angle of the Zones of the pores; Position ofthe laser beam from the surface and others if desired or required.

Various inputs may be used for adequate and accurate modeling. These caninclude, for example, pore size in μm, since pore size actually changesparameters and not just the proportions of # spots and pattern. Densitymay also be factored in, as well as surface area formula, number ofpores as related to Pore Size as per the Power Calculations, angle andlong arc in each zone of the eye sphere where each spot or row of spotswill be placed are needed, angles that will the laser spots be in foreach zone are using eye parameter inputs, and others.

In some embodiments, depth is fixed and at least two tests can besimulated, such as depth at 50%=454 μm or Depth at 80%=700 μm.

FIGS. 2K-18 and 2K-19 illustrate other exemplary microporation patterns,according to an embodiment of the disclosure.

FIG. 2K-20 is an exemplary graphical image of an exemplary embodiment ofa microporation with a pattern having 41 number of micropores, accordingto some embodiments of the present disclosure.

In some embodiments, protocol requirements for each treatment patterncan include: Spot size; Depth; Number Pores Whole Globe in AllQuadrants; Number Pores/Quadrant; Number Pores/5.5 mm patch; Volumeremoved; Density—(How many spots). Performing therapy manipulations caninclude: whole quadrant vs. patch (surface area), where specific cornealdiameter of the shape change eye can be important.

An example embodiment of applications of Artificial Intelligence,simulations and field applications may include: 1) use for R&D of theeye for various modeling implementations; 2) Virtual clinical trials; 3)Laser integration as a diagnostic companion or robotics controller; 4)Performing virtual surgery on the eye for a “Smart Surgery” plan; 5)Integration to imaging devices to improve image interpretation; 6)Integration to surgical microscope for “real time” modification ofsurgery/therapy (e.g., IOL surgery); and 7) others.

Exemplary functions of simulations can include: 1) Simulations of idealbiomechanics for optimizing total visual function and best centraloptical power for accommodation; 2) Simulations of ideal biomechanicsfor optimizing total visual function and best optical power of thecornea; 3) Simulations of ideal biomechanics for optimizing decreasedoutflow of aqueous from the trabecular meshwork; 4) Simulations of idealbiomechanics for optimizing retinal decompression of lamina cribrosa andparapapillary sclera; 5) Simulations for optimizing scleralrejuvenation; 5) Simulations for optimizing surgical outcomes of intraocular lens surgery; 6) Simulations for optimizing surgical ortherapeutic outcomes for corneal surgery; 7) Age progression simulationsto evaluate long term effects of aging on eye function; 8) Ageprogression simulations to evaluate long term stability and outcomes ofvarious surgical procedures of the eye; 9) Simulations for analyzingtesting of applications, therapies, surgical manipulation, implantationdevices and pharmacological treatments of the eye via virtual clinicaltrials; and 10) others.

In various embodiments, algorithms and other software used to implementthe systems and methods disclosed herein are generally stored innon-transitory computer readable memory and generally containinstructions that, when executed by one or more processors or processingsystems coupled therewith, perform steps to carry out the subject matterdescribed herein. Implementation of the imaging, machine-learning,prediction, automated correcting and other subject matter describedherein can be used with current and future developed medical systems anddevices to perform medical procedures that provide benefits that are, todate, unknown in the art.

In some embodiments, the described systems, methods and devices areperformed prior to or contemporaneous with various medical procedures.In some embodiments, they may be implemented in their own systems,methods and devices, along with any required components to accomplishtheir respective goals, as would be understood by those in the art. Itshould be understood that medical procedures benefitting from the hereindescribed material are not limited to implementation using the materialdescribed hereafter, but other previous, currently performed and futuredeveloped procedures can benefit as well.

Turning to FIG. 3A, an exemplary laser treatment system is illustrated,according to some embodiments of the present disclosure. In someembodiments, a treatment laser beam travels to dichroic 208. At dichroic208 the laser beam travels to Galvo Setup 320 which consists of Galvo1210 and Galvo2 212. The beam then passes from Galvo Setup 320 tofocusing optics 216 and ultimately to patient eye 140.

Also provided for in this embodiment is a control and monitoring systemwhich broadly consists of a computer 310, video monitor 312, and camera308. Camera 308 provides monitoring of the laser beam at dichroic 208via lens 306. Camera 308 transmits its feed to computer 310. Computer310 is also operable monitor and control Galvo Setup 320. Computer 310is also coupled to video monitor 312 to provide a user or operator alive feed from camera 308.

Although not shown, in some embodiments, the eye tracking system mayhave a camera near the fixation point, aimed at the treatment zone toprovide a large area view and the image of features used for eyetracking as described. This may not go through the optical systems inFIG. 3A or 3B.

In some embodiments, the second user treatment area camera may not gothrough beam focusing optics and may provide a large area image withadequate resolution to be able to provide color information down in thepore and of the entire treatment area for the user, to be displayed onthe monitor.

In some embodiments of the invention a dual axis closed loopgalvanometer optics assembly may be used.

Since multiple lasers systems may be used for treatment in someembodiments, additional laser systems will now be described.

The laser system may include a cage mount galvanometer containing aservo controller, intelligent sensor, feedback system and mount assemblywith an optical camera. Some embodiments may include use of a cage mountgalvanometer optics assembly. Some embodiments may include ultra-highresolution nano-positioners to achieve sub-nanometer resolution.

To expand, FIG. 3A shows more exemplary detail of a CCD (or CMOS)camera-based eye tracker subsystem. Dichroic 208 beam splitter may beused to pick off visible light, while allowing the IR treatment beam totransmit. The beam splitter 208 is located in front of the steeringelements, shown here as galvo mirrors 320. Lens 306 images the tissueplane (eye) onto the camera. Features in the image field (e.g. bloodvessels, edge of the iris, etc.) are identified by image processing andtheir coordinates in the camera pixel field computed. If the eye moveswithin the pixel field frame-to-frame, the change in position of thereference features can be computed. An error function is computed fromthe change in reference feature position and commands issued to thegalvo mirrors 320 to minimize the error function. In this configuration,the optical line of sight is always centered on the treatment spot,which is at a fixed coordinate in the camera pixel field. The apparentmotion from repositioning the galvos 320 will be to move the eye imagerelative to the fixed treatment spot.

FIG. 3B illustrates an exemplary laser treatment system 303 according tosome embodiments of the present disclosure. The laser treatment system303 is similar to that of FIG. 3A, except that the eye trackingsubsystem is located after galvo mirrors 320. FIG. 3B also shows anexemplary area camera image, not impacted by galvo beam steering. Thecamera may provide the eye tracking image and user visualization.

In this embodiment, a treatment laser beam travels to Galvo Setup 320which consists of Galvo1 210 and Galvo2 212. The beam then passes fromGalvo Setup 320 to dichroic 208. At dichroic 208 the laser beam travelsto focusing optics 216 and ultimately to patient eye 140.

Also provided for in this embodiment is a control and monitoring systemwhich broadly consists of a computer 310, video monitor 312, and camera308. Camera 308 provides monitoring of the laser beam at dichroic 208via lens 306. Camera 308 transmits its feed to computer 310. Computer310 is also operable monitor and control Galvo Setup 320. Computer 310is also coupled to video monitor 312 to provide a user or operator alive feed from camera 308.

Here, the eye image is shown centered in the pixel field. When eyemotion is detected within the pixel field, the galvos 320 arerepositioned to move the treatment spot to a new position within thepixel field corresponding to the movement of the eye, and to a desiredfixed position relative to the eye reference features.

The system may include a biofeedback loop, where eye tracking, in someembodiments, may include use of light source producing an infraredillumination beam projected onto an artificial reference affixed to aneye. The infrared illumination beam may be projected near the visualaxis of the eye and has a spot size on the eye greater than thereference and covering an area when the reference moves with the eye.

In some embodiments, the reference may have a retro-reflective surfacethat produces backward scattering orders of magnitude stronger thanbackward scattering from the eye would. An optical collector may beconfigured and positioned a distance from the eye to collect thisbackward scattered infrared light in order to form a bright image spotof the reference at a selected image location.

The bright image spot may appear over a dark background with a singleelement positioning detector positioned at the selected image locationto receive the bright image spot and configured to measure atwo-dimensional position of the bright image spot of the reference onthe positioning detector. An electric circuit may be coupled to thepositioning detector to produce positioning signals indicative of aposition of the reference according to a centroid of the bright imagespot based on the measured two-dimensional position of the bright imagespot on the positioning detector.

FIG. 3C illustrates an exemplary camera correction system, according toan embodiment of the present disclosure. In the example embodiment, thetop row illustrates the camera focus location after galvos have beenused and the bottom row illustrates the camera focus location beforegalvos. Various landmarks 392 may be seen in the example embodimentsincluding capillaries, iris, pupil, etc. Exemplary treatment spot 394may also be seen in each embodiment.

As is shown in the example embodiment the top row of focus before thegalvos each show the pupil of as the center pixel of each image.Compensation after galvos in the bottom row allows the treatment spot394 to remain the focus of the camera's attention in each image andthereby allow the system to remain in position for the associatedprocedure.

In some embodiments, the camera may be positioned to support eyetracking system separate for the main laser optical system, near thefixation point. This may still allow the camera to center the pixelimage on the treatment area and support the intended compensation. Thismay allow using a camera as part of the main laser optical system afterthe galvos to work as stated above.

FIG. 3D illustrates an exemplary flow diagram 330 of a camera-based eyetracker process, according to some embodiments of the presentdisclosure.

Broadly put, the diagram represents the use of a camera, for example, aCCD or CMOS camera to capture an image of eye. The image may be incolor. Image data is transmitted to a computer, where key features aresegmented/extracted (e.g. blood vessels, iris features, edge of pupil).The image is stored as a reference frame. Subsequent images are thencompared to the reference frame. Any shift is computed after comparingreference features in pixel coordinates. Conversion of pixel coordinatesto scanning system coordinates then occurs before commanding thescanning (or treatment laser beam pointing) system to deviate treatmentbeam line of site to restore relationship relative to referencefeatures. If the shift is too large or out of range of the scanningsystem, the procedure may be halted and take steps may be taken toreacquire the target image field.

In some embodiments, the system may not utilize galvo scanning mirrorsand utilize a multi-axis motion control system to position the laser foreach pore (see, e.g., FIG. 20H). This may provide coordinate measuring.

In some embodiments, an initialization or starting sequence may requirecapturing image frame in step 332 before processing the captured imageframe in order to extract features in step 334. This captured frame withextracted features is then used to set a reference frame in step 336.

After a reference frame is set, step 338 may consist of capturing anadditional image frame, called a current frame, according to someembodiments. This image or current frame is processed in step 340 inorder to extract features. Step 342 may include comparing the currentframe to the reference frame which was set in step 336. Any image shiftis computed between the current frame and the reference frame in orderto determine the difference between the frames. A comparison to apre-set threshold allows the system to determine if the image shiftexceeds the pre-set threshold and stops the procedure at this point bygoing to step 352.

If an image shift does not exceed the pre-set threshold and therefore isnot too large, the system may compute a compensation level in step 346in order to compensate for the change or shift between the current frameand the reference frame. This compensation level is computed intophysical coordinates used by a scanner in step 348. The scanner may thencommand to compensate using the coordinates in step 350. After thiscompensation step 338 occurs and another current image frame iscaptured, and the cycle may continue.

FIG. 4A illustrates an exemplary laser treatment system 400 according tosome embodiments of the present disclosure. In the example embodiment,laser treatment system 400 may include a treatment laser 202 emitting alaser beam which travels through relay lens 204 to dichroic or flip-in208. Visible spotting laser 206 emits a laser beam which also travels todichroic or flip-in 208. In some embodiments, the beams from treatmentlaser 202 and visible spotting laser 206 may meet simultaneously atfirst dichroic or flip-in 208. In other embodiments, the beams may reachfirst dichroic or flip-in 208 at staggered times.

The beam or beams leave first dichroic or flip-in 208 and travels to asecond dichroic 208. The beam or beams leave second dichroic 208 andtravel to Galvo 210. Galvo1 210 may include a mirror which rotatesthrough a galvanometer set-up in order to move a laser beam. The beam orbeams leave Galvo 210 and travel to Galvo2 212 which may be a similarsetup to Galvo1 210. The beam or beams leave Galvo2 212 and travel todichroic (visible/IR) 214. In some embodiments, an operator 160 maymonitor the beam or beams at dichroic (visible/IR) 214 by using asurgical microscope 150. The beam or beams travel from dichroic(visible/IR) 214 through focusing optics 216 to patient eye 140.

Still in FIG. 4A, additional monitoring elements may be provided for useby operator 160 to aid in medical procedures. Depth control subsystem302 assists in controlling the depth of ablation procedures inaccordance with some embodiments of the present disclosure, and receivesinput from second dichroic 208. FIGS. 4A-1 to 4A-10 illustrate howmicroporation/nanoporation may be used to remove surface, subsurface andinterstitial tissue and affect the surface, interstitial, biomechanicalcharacteristics (e.g., planarity, surface porosity, tissue geometry,tissue viscoelasticity and other biomechanical and biorheologicalcharacteristics) of the ablated target surface or target tissue.

Similarly, eye tracker 304 may assist in tracking landmarks on patienteye 140 during medical procedures in accordance with some embodiments ofthe present disclosure, and receives input from second dichroic 208.Another dichroic 208 is shown in the example embodiment splitting thebeam with outputs to eye tracker 304 and depth control subsystem 302.

FIG. 4B-1 illustrates an exemplary laser treatment system includingablation pore depth according to some embodiments of the presentdisclosure. FIG. 4B-1 generally shows a treatment laser beam travelingto dichroic 208 before travelling to Galvo 210, then to Galvo 212,through focusing optics 216, and to patient eye 140. As shown above,FIGS. 4A-1 to 4A-10 illustrate how microporation/nanoporation may beused to remove surface, subsurface and interstitial tissue and affectthe surface, interstitial, biomechanical characteristics (e.g.,planarity, surface porosity, tissue geometry, tissue viscoelasticity andother biomechanical and biorheological characteristics) of the ablatedtarget surface or target tissue.

In some embodiments, system 404, which may be an Optical CoherenceTomography (OCT) system, may be used to obtain subsurface images of theeye. As such, when coupled to computer 310 which is coupled to videomonitor 312, system 404 provides a user or operator the ability to seesubsurface images of the tissue ablation. As noted herein, pore ablationcan be between 5% and 95% of the sclera thickness, with average sclerathickness as 700 μm a typical pore depth could be magnitudes of orderlarger than refractive surface ablation at around 200 μm-300 μm deep.This is significantly greater depth than other surface refractiveablative procedures that are typically between 10 μm-45 μm in depth onaverage and generally >120 μm.

In at least some embodiments, system 404 may provide a real-time,intraoperative view of depth levels in the tissue. System 404 mayprovide for image segmentation in order to identify sclera interiorboundary to help better control depth. As shown and mentioned above,FIGS. 4A-1 to 4A-10 illustrate how microporation/nanoporation may beused to remove surface, subsurface and interstitial tissue and affectthe surface, interstitial, biomechanical characteristics (e.g.,planarity, surface porosity, tissue geometry, tissue viscoelasticity andother biomechanical and biorheological characteristics) of the ablatedtarget surface or target tissue.

In some embodiments, system 404 may use an OCT measurement beam,injected into the treatment beam line of sight via a dichroic beamsplitter 208, located before the scanning system. In this way, the OCTsystem line of sight is always centered on the pore being ablated.System 404 may be connected to a computer 310 for processing the imagesand for control of the laser.

In some embodiments of the present disclosure, an anatomy avoidancesubsystem is provided to identify critical biological obstacles orlocations during procedures (e.g. blood vessels and others). As such,subsurface visualization may be provided to identify obstacles such asblood vessels or anatomy that is desired to be avoided intraoperatively.

FIG. 4A-5 and FIG. 4B-2 show exemplary simplified diagrams of anablation pore in the sclera showing an example of the depth of anablation in relation to the inner boundary of the sclera.

FIG. 5 illustrates an exemplary flow diagram of depth control process410, according to some embodiments of the present disclosure.

In general, the depth-control system, e.g., an OCT system executes arepetitive B-scan, synchronized with the laser. The B-scan may show thetop surface of the conjunctiva and/or sclera, the boundaries of the porebeing ablated, and the bottom interface between the sclera and thechoroid or ciliary body. Automatic image segmentation algorithms may beemployed to identify the top and bottom surfaces of the sclera (forexample, 400-1000 microns thick) and the boundaries of the ablated pore.The distance from the top surface of the sclera to the bottom surface ofthe pore may be automatically computed and compared to the localthickness of the sclera. In some embodiments, this occurs in real time.When the pore depth reaches a predefined number or a fraction of sclerathickness, ablation may be halted, and the scanning system indexed tothe next target ablation location. In some embodiments, images may besegmented to identify interior sclera boundaries.

With reference to the steps in the figure, in the example embodiment astarting or initialization set of steps may occur first. This startingset of steps begins with positioning to a pore coordinate in step 412.AB-scan of the target region occurs in step 414. This scan creates animage which is processed in step 416 in order to segment and identifythe sclera boundary. A distance is then computed in step 418 between theconjunctive surface and the sclera boundary.

After completion of this starting set of steps ablation may be initiatedin step 420. A laser beam pulse is fired in step 422 followed by aB-scan in step 424. This B-scan creates an image that may then besegmented in step 426 and pore depth and ablation rate are computed fromthe image. This pore depth and ablation rate are compared to the targetdepth in step 430. If the target depth has not been reached, then theprocess loops back to step 422 and repeats. Upon reaching a targetdepth, step 432 stops the ablation process and the starting processbegins again at step 434 with positioning to next pore coordinates. Insome embodiments, the depth-control system can monitor ablation depthduring a single pulse and can stop the ablation as a risk mitigationmeans, there may also be other internal processes running that can endthe ablation if the process is out of range; eye tracking operationallimits exceeded, max preset # of pulses exceeded, laser power monitoringis not in limits. All of these are risk mitigation measures.

FIG. 6 illustrates an exemplary laser treatment system component diagram600 showing relation of related subsystems according to some embodimentsof the present disclosure.

In general laser treatment system component 600 may include a laser 602,a laser delivery fiber 120, laser control system 604, monitoring system608, and beam control system 606.

Laser 602 may generally be made up of several subsystems. In the exampleembodiment, these subsystems include system control electronics 104,Er:YAG laser head 612, laser cooling system 108, HV power supply 110,and system power supplies 112. Foot pedal 114 provides some control forthe system user. Laser 602 transmits a laser beam via laser deliveryfiber 120 to beam control system 606.

Beam control system 606 may generally be made up of beam transportoptics 624, red spotting laser 626, galvo mirrors 628, beam deliveryoptics 630, and active focus 632.

Laser control system 604 maintains a link to laser 602 via a laser syncand to beam control system 606 via power control position status. Lasercontrol system 604 may generally be made up of a user interface 614,power supply 616, galvo controller 618, galvo controller 620, andmicrocontroller 622. Laser control system 604 may also be manipulatablevia joystick 610.

Monitoring system 608 may generally be made up of camera 634 (e.g., aCCD or suitable camera), and visual microscope 636.

In some embodiments, a fiber laser may be composed of an undopedcladding and a doped core of higher refraction. The laser beam travelsthrough the fiber guided within the fiber core and experiences a highamplification due to the length of interaction. Fiber lasers areconsidered advantageous to other laser systems because, among otherqualities, they have simple thermal management properties, high beamquality, high electrical efficiency, high optical efficiency, high peakenergy, in addition to being low cost, requiring low maintenance, havingsuperior reliability, a lack of mirror or beam path alignment, and theyare lightweight and generally compact.

In some embodiments of the present disclosure, spot arrays may be usedin order to ablate multiple pores at once. These spot arrays may, insome cases, be created using microlenses and also be affected by theproperties of the laser. A larger wavelength may lead to a smallernumber of spots with increased spot diameter.

Turning to FIG. 7, an exemplary laser treatment system 700 is shownaccording to some embodiments of the present disclosure. Laser treatmentsystem 700 may generally be made up of control system 702, optics andbeam controls.

Control system 702 may include monitor 704 and monitor 706, as well askeyboard 708 and mouse 710 to provide a user the ability to interact andcontrol with a host computer 724 running computer programs. In manyembodiments, the computer programs running on host computer 724 includecontrol programs for controlling visible spotting laser 712, laser head714, laser cooling system 716, system power supplies 718, laser powersupply 720, and beam transport optics 722.

Also provided for in this embodiment are depth control subsystem 726,galvo mirrors 728, camera 730 (e.g., CCD camera, or suitable camera),visual microscope 732, focus subsystem 734, and beam delivery optics736.

FIG. 7-1 illustrates another exemplary laser treatment system, accordingto some embodiments of the present disclosure.

Turning to some other aspects of the present disclosure, preoperativemeasurement of ocular properties and customization of treatment to anindividual patient's needs is beneficial in many embodiments.Preoperative measurement of ocular properties may include measuringintraocular pressure (IOP), scleral thickness, scleral stress/strain,anterior vasculature, accommodative response, and refractive error.Measurement of scleral thickness may include use of optical coherencetomography (OCT). Measurement of scleral stress/strain may include usingBrillouin scattering, OCT elastography, photoacoustics (light plusultrasound). Measurement of anterior vasculature may include using OCTor Doppler OCT. Measurement of refractive error may include using theproducts such as the iTrace trademarked product from Tracey TechnologiesCorp. Those of ordinary skill in the art will recognize that othermeasurements, methods and systems may also be used.

Intraoperative biofeedback loops may be important during a treatmentprocedure in order to keep the physician informed on the progress of theprocedure. Such feedback loops may include use of topographicalmeasurements and monitoring “keep away” zones such as anterior ciliaryarteries.

Biofeedback loops may include a closed-loop sensor to correct fornonlinearity in the piezo scanning mechanism. The sensor in someembodiments may offer real-time position feedback, e.g., in a fewmilliseconds and utilizing capacitive sensors for real-time positionfeedback. Real-time position feedback may be communicated to acontroller, and, upon identification of specific biological featuresbased on tissue characteristics, may cease laser operationintraoperatively.

Sensor/feedback apparatus may also perform biological or chemical “smartsensing” to allow ablation of target tissue and protect or avoidsurrounding tissue. In some instances, this smart sensing may beaccomplished by using a biochip incorporation in a mask which isactivated by light irradiation and senses location, depth, size, shape,or other parameters of an ablation profile. Galvo-optic assemblies arealso contemplated in some embodiments and may be used to gage numerousparameters of laser steering and special function.

Those of ordinary skill in the art will recognize that other feedbackmethods and systems may also be used.

In some embodiments, the systems, methods and devices of the presentdisclosure may include image display transfer and GUI interface featuresthat can include each image frame taken and send information to a videodisplay after each firing inside the 3-dimension-7-dimension microporebefore and after the firing of the laser in dynamic real time andsurface view. The GUI may have integrated multiview system in7-directionality for image capture including: surface, internal pore,external pore, bottom of the micropore, whole globe eye view, targetarray area.

In some embodiments, 7-cube may be a preferred projection for themicroprocessor but other examples exist in dimensional sphere shape,integrated into the GUI and microprocessor. Orthogonal projections caninclude examples as shown in FIG. 8.

In some embodiments, support vector machine (SVM) pattern recognitionmay be integrated into the AI (artificial intelligence) network directedto the microprocessor path. For the non-linear classification problem,the SVM may turn the input space into a high dimensional space by anonlinear mapping K(X). Hence, the nonlinear problem may turn into alinear problem and then the optimal separating hyperplane will becalculated in a new high dimensional space, e.g., using Matlab orMathematica integrated programming. As the optimization functions andclassification functions involve only the inner product between samples(xi−xe) the transformed higher dimensional space is also just the innerproduct (k(xi)−k(xe)). If the kernel function k(xi−k(xe) satisfies withMercer condition, it corresponds to a transform space of inner product K(xi, x=(k(xi)−k(x)). The common kernel functions include linear kernelpolynomial kernel and radial bias kernel function. The use ofappropriate kernel function can be an alternative to non-linear mappingof high dimensional space, which will achieve a linear classificationafter nonlinear transformation. The corresponding classificationdiscriminant function can be obtained as follows:

$\begin{matrix}{{g(x)} = {{sgn}\left( {{\sum\limits_{i = 1}^{n}{\alpha_{i}^{*}{y_{i}\left( {x_{i} \cdot x} \right)}}} + b^{*}} \right)}} \\{= {{sgn}\left( {{\sum\limits_{x_{i} \in {SV}}{\alpha_{i}^{*}{y_{i}\left( {x_{i} \cdot x} \right)}}} + b^{*}} \right)}}\end{matrix},$

In some instances, mapping and optimization formulas for machinelearning may include:

$\begin{matrix}{{{g(x)} = {{{sgn}{\sum\limits_{i = 1}^{n}{\alpha^{*}{y_{i}\left( {x_{i}*x} \right)}}}} + {b^{*}\text{)}}}}{{g(x)} = {{{sgn}{\sum\limits_{i = 1}^{n}{\alpha^{*}{y_{i}\left( {x_{i}*x} \right)}}}} + {b^{*}\text{)}}}}{{g(x)} = {{sgn}\left( {{\sum{\alpha i^{*}yi{K\left( {xi \times x} \right)}}} + b^{*}} \right)}}} & \;\end{matrix}$

Instrument of the GUI interface and code may include multi-dimensionalscaling, linear discriminant analysis and linear dimensional reductionprocessing as well as locally linear embedding and isometric maps(ISOMAP) and nonlinear dimensionality reduction methods may also beincluded.

In some embodiments, continuous mapping p: E→B satisfying the homotopylifting property with respect to any space may be used. Fiber bundles(over paracompact bases) constitute important examples. In homotopytheory, any mapping may be ‘as good as’ a fibration—i.e. any map can bedecomposed as a homotopy equivalence into a “mapping path space”followed by a fibration into homotopy fibers.

The fibers are by definition the subspaces of E that are the inverseimages of points b of B. If the base space B is path connected, it is aconsequence of the definition that the fibers of two different points b₁and b₂ in B are homotopy equivalent. Therefore, one usually speaks of“the fiber” F.

Some embodiments can utilize a Serre fibration or Weak fibration. Theyare able to produce mapping of each cylinder micropore in the array andthe total array across the 3D surface and interstitial mapping of porearrays in cross section. An exemplary 3D mapping 900 is shown in FIG. 9.

FIG. 10 illustrates, according to some embodiments of the presentdisclosure, exemplary design patterns that can be performed as follows.Step 1001: Treatment design/planning may begin with tissue hierarchywhich is established using the 7-Sphere mathematical projection overentire sphere to establish congruent treatment platform built on 7Dshape and hyperbolic planar tessellation. Step 1002: Off Axismathematical algorithm derived from tissue hierarchy and Fibonaccipatterning is displayed as mathematical imagery. Step 1003: AlgorithmicCode is then implemented to develop customized microporation patternsthat are reflective of the tissue biorheology including all inputs ofrigidity, viscoelastic modulus, topology, topography, biometry etc. Step1004 (not shown): Anatomy avoidance software may be executed erasing oreliminating untargeted fields, arrays, regions. Step 1005 (not shown):Surgeon/user can also manipulate the targeted or untargeted areas viatouch screen interface.

In some embodiments, the described systems, methods and devices of thepresent disclosure may include the following features of laser userinterface system delivery of treatment algorithms. Real timemathematical imagery is incorporated and displayed both in 3Dmathematical files which can also be run in a GIF animation format todisplay apriori information regarding the array effectiveness. Theworkstation/algorithms work together with the VESA system in order toproduce the mathematical imagery to the user/surgeon for idealconfiguration of the 3D array on the eye. The topological representationof the image is projected stereographically to the display. The array isprefixed formularies and in addition can be simulated in Fibonaccisequencing with a plurality of densities, spot sizes, micro and nanopore geometries and configurations. The benefit of the Fibonaccisequencing is to produce the most balanced array formulary whichcorresponds to the body's own natural tissue hierarchy both in macro andmicro scales.

The array can also follow a hyperbolic geometry model or a uniform(regular, quasiregular, or semiregular) hyperbolic tiling which is anedge-to-edge filling of the hyperbolic plane which has regular polygonsas faces and is vertex-transitive (transitive on its vertices, isogonal,i.e. there is an isometry mapping any vertex onto any other). Examplesare shown in FIGS. 10 and 11. It follows that all vertices arecongruent, and the tiling has a high degree of rotational andtranslational symmetry.

The uniform tilings can be identified by their vertex configuration, asequence of numbers representing the number of sides of the polygonsaround each vertex. One example below represents the heptagonal tilingwhich has 3 heptagons around each vertex. It is also regular since allthe polygons are the same size, so it can also be given the Schläflisymbol. The uniform tilings may be regular (if also face- andedge-transitive), quasi-regular (if edge-transitive but notface-transitive) or semi-regular (if neither edge- nor face-transitive).For right triangles (p q 2), there are two regular tilings, representedby Schläfli symbol {p,q} and {q,p}.

Exemplary models are illustrated in FIG. 11.

In some embodiments, the described systems, methods and devices of thepresent disclosure may include mechanism of creating an array ofmicropores the micropore array pattern having a controlled non-uniformdistribution, or a uniform distribution, or a random distribution, andmay be at least one of a radial pattern, a spiral pattern, aphyllotactic pattern, an asymmetric pattern, or combinations thereof.The phyllotactic spiral pattern may have clockwise and counterclockwiseparastichy according to the present disclosure. FIG. 12 illustrates anexemplary schematized representation 1200 of creation of an asymmetricalcontrolled distribution of an array algorithm pattern on an eye withspiral phyllotaxis, where each array of micropore successively appear.R₀ is the radius of the region that corresponds to the center of themeristem around which the micropores are generated. The big verticalarrow 1210 symbolizes vertical microporation expansion in the array,while the laterally depicted arrows 1220, 1230 indicate the spatialexpansion of the system of new micropores. i and j are pairs ofsuccessive Fibonacci numbers, i.e. such a pair of successive Fibonaccinumbers is indicated as (i, j). The symbols n, n−i, n−j, n−i−j stand fornumbers indicating the order of appearance of micropores along thegenerative spiral during expansion of the array. However, they maybetter be symbolized by n, n+i, n+j, n+i+j. There are consecutivenumbers in one and the same family of secondary spirals display aconstant difference between them. So, for the anticlockwise family:(n+i)−n=i, which is a Fibonacci number. (n+i+j)−(n+j)=i, which is thesame Fibonacci number. For the clockwise family: (n+j)−n=j, which is thesecond Fibonacci number. (n+i+j)−(n+i)=j, which is the same Fibonaccinumber. So here we have a case of (i, j) phyllotaxis.

In some embodiments, the micropore array pattern may be one of anArchimedean spiral, a Euler spiral, a Fermat's spiral, a hyperbolicspiral, a lituus, a logarithmic spiral, a Fibonacci spiral, a goldenspiral, or combinations thereof.

In some embodiments, the described systems, methods and devices of thepresent disclosure may include creation of a 3D microporation model on aspherical surface. FIG. 13 illustrates an exemplary graphical image 1300created on CAD program of an exemplary embodiment of a microporationwith a pattern having a mechanism of creating the micropore array andexpanding the microporation array in radial and lateral directionsutilizing phyllactic spiral to expand the array face to face and edge toedge while mainlining a non-uniform distribution through divergenceangels consistent with the Vogel Model and Fibonacci sequence wherein Xnumber of micropores at a plurality of densities, sizes and geometricshapes are created according to the present invention. Although thisexample embodiment is the anterior or posterior sclera of the eye, itcould also be the cornea.

In some embodiments, the described systems, methods and devices of thepresent disclosure may include utilization of Fibonacci and mathematicalparameters to optimize surgical execution, outcomes and safety in alaser assisted microporation treatment array having a pattern ofmicropores/nanopores, wherein the pattern is a non-uniform distributionpattern that is delivered in cross sectional tissue in alignment withthe existing tissue hierarchy on a macro scale and microscale so thatthere is a congruent rejuvenation effect of the treatment. A treatmentarray or lattice having a plurality ofmicropores/nanopores/ablations/incisions/targets may be arranged in anon-uniform distribution pattern, wherein the pattern is spiral orphyllotactic. The patterns may be described by the Vogel equation. Also,included is a plurality of other geometries/densities/depths and shapeshaving a spiral or phyllotactic patterns of flow paths, such as in theform of open channels or pores. The micropores/nanopores can bespecifically adapted to correspond with any given contact lens, mask orother template material or design having a non-uniform distributionpattern. Alternatively, the microporation can be used in conjunctionwith conventional perforated coated or non-coated polymers such ashydrophilic or hydrophobic types. The array pattern having a non-uniformdistribution pattern of micropores and the lens or mask can be usedtogether as a treatment system.

As shown above, FIGS. 4A-1 to 4A-10 and also FIG. 26-3A illustrate howmicroporation/nanoporation may be used to remove surface, subsurface andinterstitial tissue and affect the surface, interstitial, biomechanicalcharacteristics (e.g., planarity, surface porosity, tissue geometry,tissue viscoelasticity and other biomechanical and biorheologicalcharacteristics) of the ablated target surface or target tissue.Additionally, the present disclosure may include various types ofautomated processing systems to process the delivery of microporationsof various compositions and configurations.

Tissue characteristics effected include, among others, porosity,texture, viscoelasticity, surface roughness, and uniformity. Surfacecharacteristics, such as roughness and gloss, are measured to determinequality. Such microporation can also affect tissue deformation,pliability and flexibility and have an “orange peel” texture. Hence, theproperties of the tissue treated with microporation/nanoporation willgenerally influence and/or enhance the tissue quality by means ofrestoring or rejuvenating the biomechanical pliability of the tissuewhen at rest and under stress/strain.

In some embodiments, microporation can include a plurality of microporepaths disposed in a pattern. The pattern of micropore paths can compriseregular polygons, irregular polygons, ellipsoids, arcs, spirals,phyllotactic patterns, or combinations thereof. The pattern of microporepaths can comprise radiating arcuate paths, radiating spiral paths, orcombinations thereof. The pattern of micropore paths can comprise acombination of inner radiating spiral paths and outer radiating spiralpaths. The pattern of air flow paths can comprise a combination ofclock-wise radiating spiral paths and counter clock-wise radiatingspiral paths. The micropore paths can be discrete, or discontinuous,from each other. Alternatively, one or more of the micropore paths canbe fluidly connected. The number of radiating arcuate paths (“arcs”),radiating spiral paths, or combinations thereof can vary.

In some embodiments, microporation can comprise a pattern that is acontrolled nonlinear distribution pattern, a controlled lineardistribution pattern or a random pattern. In some embodiments, eyecontact lens/eye mask can comprise a pattern of micropore paths whereinthe pattern of micropore paths is generated from x and y co-ordinates ofa controlled non-uniform distribution pattern. The controllednon-uniform distribution pattern used to generate the eye lens/eye maskmicropore path can be the same or different than the array pattern ofthe laser microporation algorithm being used with the eye lens/eye mask.In an embodiment, the controlled non-uniform distribution pattern is thesame as the array pattern of the laser microporation algorithm beingused with the eye lens/eye mask. In some embodiments, the controllednon-uniform distribution pattern is different than the array pattern ofthe laser microporation algorithm being used.

In some embodiments, the laser microporation system may havephyllotactic patterns according to the laser microporation algorithmembodiments described herein. An eye lens/eye mask is co-operative witha laser microporation system having phyllotactic patterns when the lasermicroporation system includes a plurality of micropores, a plurality ofopenings, a plurality of cavities, a plurality of channels, plurality ofpassages, or combinations thereof, that are configured in a patterndesigned to promote improvement of natural biological functions such asfluid flow, blood flow, muscular movement, as well as static and dynamicbiological function through the eye lens/eye mask and tissue having aphyllotactic pattern. The micropores, openings, cavities, channels,passages, or combinations thereof can define biological flow paths thatare located along, within, or though the back-up pad, or combinationsthereof. In an embodiment, the pattern of micropores, openings,cavities, channels, passages or combinations thereof can be in the formof a regular polygons, irregular polygons, ellipsoids, arcs, spirals,phyllotactic patterns, or combinations thereof. In another embodiment,the air-flow paths can be in the form of a regular polygons, irregularpolygons, ellipsoids, arcs, spirals, phyllotactic patterns, orcombinations thereof.

In some embodiments, a suitable spiral or phyllotactic pattern can begenerated from the x and y co-ordinates of any phyllotactic arraypattern of the microporation system embodiments described above. In anembodiment, the x and y co-ordinates of a spiral or phyllotactic patternare transposed and rotated to determine the x′ and y′ co-ordinates ofthe spiral or phyllotactic back-up air flow pattern, wherein θ is equalto it/n in radians and n is any integer. The (x′ and y′) can be plotted,such as by the use of computer aided drafting (CAD) software, togenerate a suitable pattern such as a spiral or phyllotactic pattern.

The patterns can then be used to define radiating accurate and spiralchannels, as well as, annular channels that can intersect the arcuateand spiral channels, or combinations thereof. The annular, arcuate,spiral, or combination channels can produce shape deformation, such asin the form of grooves, cavities, orifices, passages, or other pathwaysto form. Exemplary embodiments of channel patterns that are based ontransposed phyllotactic patterns are also shown in FIGS. 10, 13, and 16.Additional exemplary embodiments based on transposed phyllotacticpatterns are shown in FIGS. 14A-14D, 15A-15F, and 41.

As shown below, microporation pattern may have a number of clockwisespirals and a number of counter-clockwise spirals, wherein the number ofclockwise spirals and the number of counterclockwise spirals areFibonacci numbers or multiples of Fibonacci numbers.

FIG. 14A illustrates an exemplary embodiment of a microporation patternwhich can be implemented directly on the target tissue or alternativelyon a contact lens, mask, or other such template having an microporepattern with a controlled non-uniform distribution of the micropores inthe distribution of the Fibonacci sequence, according to someembodiments of the present disclosure.

FIG. 14B is an exemplary illustration of a phyllotactic spiral patternhaving clockwise and counterclockwise parastichy, according to someembodiments of the present disclosure.

FIG. 14C is another exemplary illustration of a phyllotactic spiralpattern having clockwise and counterclockwise parastichy, according tosome embodiments of the present disclosure.

FIGS. 14D and 14E are exemplary illustrations of the Vogel model, inaccordance with some embodiments of the present disclosure. The Vogelmodel includes the pattern of florets. Briefly, each floret is orientedtowards the next at about 137.5°. The number of left spirals and thenumber of right spirals are Fibonacci numbers. The sunflower pattern hasbeen described by Vogel's model, which is a type of “Fibonacci spiral”,or a spiral in which the divergence angle between successive points is afixed Fibonacci angle that approaches the golden angle, which is equalto 137.508°. In an exemplary sunflower pattern, there are 34 in onedirection and 55 in the other.

FIGS. 15A-15F are exemplary illustrations of phyllotactic spiralpatterns conforming to the Vogel model that have differing divergenceangles, according to some embodiments of the present disclosure.

FIGS. 16A-16N are exemplary illustrations of exemplary embodiments ofmicroporation derived from icosahedron pattern shapes, according to someembodiments of the present disclosure.

FIGS. 17A-17B, and also FIGS. 2K-18 and 2K-19 as shown above, areexemplary illustration of microporation patterns derived fromicosahedron pattern shapes representing a fractal sphere andicosahedron/tetrahedron tessellations, according to some embodiments ofthe present disclosure.

In some embodiments, the exemplary microporation patterns, for exampleas illustrated in FIGS. 14A to 17B above may be pre-drilled in tocontact lens or mask. FIG. 18 illustrates an exemplary contact lens/eyemask that is co-operative with a microporation pattern.

In some embodiments, the micropore pattern is described by the Vogelmodel or a variation of the Vogel model. The Vogel model is φ=n*a,r=c√n, where: n is the ordering number of an micropore, counting outwardfrom the center of the micropore pattern; φ is the angle between areference direction and a position vector of the nth micropore (e.g., afloret) in a polar coordinate system originating at the center of themicropore pattern (e.g., a capitulum), such that the divergence angle,α, between the position vectors of any two successive micropores is aconstant angle α; r is the distance from the center of the microporepattern to the center of the nth micropore; and c is a constant scalingfactor.

In some embodiments, all, substantially all, or a portion of themicropores of the micropore pattern will be described by (i.e., conformto) the Vogel model. In some embodiments, all the micropores of themicropore pattern may be described by the Vogel model. In some otherembodiments, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, or at least 99% of the micropores may bedescribed by the Vogel model.

Surface Area:

The total target tissue surface area affects the amount total tissuematerial removed. Typically, as the amount of total tissue surface areais increased, the amount of surface material removed is increased. Insome embodiments, the total microporation surface area of the targettissue may be equal to the total potential surface of the microporationsystem (i.e., the microporation target area if there were no micropores)minus the total micropore area (i.e., the sum of the area of all themicropores). Thus, the amount of the total microporation surface areacan range from 1% to about 99.5% of the total potential surface area,depending on the amount of desired micropore area. See FIG. 30 forexemplary surface areas, according to some embodiments of the presentdisclosure.

Depth:

Referring back to FIGS. 4A-5 to 4A-10, they illustrate that the totaltarget tissue depth may affect the amount of total tissue materialremoved. Generally, as the amount of total tissue depth is increased,the amount of interstitial or subsurface tissue removed is increased. Insome embodiments, the depth of the tissue microporation removed is equalto the total potential subsurface and interstitial tissue of themicroporation system (i.e., the total interstitial and subsurface tissueif there were no micropores) minus the total micropore cubic volume(i.e., the sum of the area of all the micropores). Thus, the amount ofthe total microporation cubic volume can range from 1% to about 95% ofthe total potential subsurface and interstitial cubic volume of themicroporation tissue, depending on the amount of desired micropore cubicvolume.

Density of Micropores:

The density of the micropore array may influence the total amount ofmicropore area and the total amount of surface, subsurface, andinterstitial volume removed. It also may influence the total number ofmicropores and micropore distribution. A plurality of exemplary densityconfigurations, micropore size and distribution of micropores areillustrated in FIGS. 2K-1-A to 2K-1-C and through 2K-17 above. It shouldbe noted that micropores can be delivered randomly, uniformly, orsingularly.

Number of Micropores:

The number of micropores may influence the total amount of microporearea and the amount of total surface, subsurface, and interstitialvolume removed. Additionally, the number of micropores may affect thedensity and distribution of micropore coverage on the surface of themicroporation, which in turn may directly affect the total volumeextraction of the microporation. In some embodiments, the number ofmicropores may be at least about 3, at least about 5, at least about 8,at least about 12, or at least about 15. In some other embodiments, thenumber of micropores may be at least about 45, at least about 96, atleast about 151, or at least about 257. For other parameters, see alsoFIGS. 31-34, 37, 38, and 39.

In some embodiments, the number of pores can range between 36 to 10,000pursuant to the size of the spot which can range from 1 nm-600 μm. Thenumber of micropores can be within a range comprising any pair of theprevious upper and lower limits.

Various parameters and factors may influence the microporation of thepresent disclosure and are illustrated in FIGS. 31-35, and alsodiscussed below.

Divergence Angle:

In delivering the laser pulse to the target tissue, increasing ordecreasing the divergence angle α may affect how the micropores areplaced within the pattern and the shape of the clockwise andcounterclockwise spirals. The divergence angle is equal to 360° dividedby a constant or variable value, thus the divergence angle can be aconstant value, or it can vary. In some embodiments, the pattern mayhave a divergence angle in polar co-ordinates that ranges from about100° to about 170°. Small changes in divergence angle can significantlyalter the array pattern and may show phyllotactic patterns that differonly in the value of the divergence angle. An exemplary divergence anglemay be 137.3°. The divergence angle may also be 137.5°, or 137.6°. Insome embodiments, the divergence angle is at least about 30°, at leastabout 45°, at least about 60°; at least about 90°, or at least about120°. In other embodiments, the divergence angle is less than 180°, suchas not greater than about 150°. The divergence angle can be within arange comprising any pair of the previous upper and lower limits. Insome other embodiments, the divergence angle ranges from about 90° toabout 179°, about 120° to about 150°, about 130° to about 140°, or about135° to about 139°. In some embodiments, the divergence angle isdetermined by dividing 360° by an irrational number. In someembodiments, the divergence angle is determined by dividing 360° by thegolden ratio. In some embodiments, the divergence angle is in the rangeof about 137° to about 138°, such as about 137.5° to about 137.6°, suchas about 137.50° to about 137.51°. In some embodiments, the divergenceangle is 137.508°.

Distance to the Edge of the Microporation Array:

In some embodiments, the overall dimensions of the array pattern can bedetermined based on the geometry of the microporation and intendedusage. The distance from the center of the pattern to the outermostmicropores can extend to a distance coterminous with the edge of themicroporation. Thus, the edges of the outermost micropores can extend toor intersect with the edge of the microporation. Alternatively, thedistance from the center of the pattern to the outermost micropores canextend to a distance that allows a certain amount of space between theedges of the outermost micropores and the edge of the microporation tobe free of micropores. The minimum distance from the edges of theoutermost micropores can specified as desired. In some embodiments, theminimum distance from the edges of the outermost micropores to the outeredge of the microporation is a specific distance, identified as adiscreet length or as a percentage of the length of face of themicroporation upon which the array pattern appears.

Size of Micropores:

In some embodiments, the size of the micropores may be determined, atleast in part, by the desired total amount of array area for themicroporation. The size of the micropores can be constant throughout thepattern or it can vary within the pattern. In some embodiments, the sizeof the micropores is constant. In some embodiments, the size of themicropores varies with the distance of the micropores from the center ofthe pattern. The size of the pores can range from 1 nm-600 μm. In someother embodiments, the size is 50 μm, 100 μm 125 μm, 200 μm, 250 μm, 325μm, 425 μm, or 600 μm.

Shape of Micropores:

Shape of micropores themselves created in connective tissue byelectromagnetic irradiation may have relative consequence on the tissuereaction and wound healing. Square shapes may heal slower than roundshapes. The microporation system is capable of creating a plurality ofgeometric individual micropore shapes. In some embodiments, the idealshape is square.

Shape may also be impactful in the micropore array. The amount ofcoverage can be influenced by the shape of the micropores. The shape ofthe micropores can be regular or irregular. In some embodiments, theshape of the micropores can be in the form of slits, regular polygons,irregular polygons, ellipsoids, circles, arcs, spirals, channels, orcombinations thereof. In some embodiments, the micropore arrays have theshape of a circle. In some embodiments, the shape of the array may be inthe form of one or more geometric patterns, for example, icosahedron ortetrahedron tessellations, wherein multiple polygons intersect.

FIGS. 16A-N show examples of such shaped micropore arrays. The microporearrays are configured such that the patterns resemble polygons, whichcan have slightly accurate edges. Tissue removal in these configurationseffect biomechanical properties in a mathematically and geometricallybalanced way producing stability to the microporation.

Design Factor: The design factor may influence the overall placement ofthe microporation array or lattice in 3D tissue and relative tomicroporation edges with relation to the ‘atmosphere’ within the tissue.The design of the microporation can be adjusted depending on theinherent shape of the tissue itself or around the intended physiologicalanatomy or desired impact. This can be a self-dual (infinite) regularEuclidean honeycombs, dual polyhedron, 7 cube, 7 orthoplex or likewisesimple lattice, Bravais lattice, or non-Bravais lattice.

Scaling Factor:

The scaling factor may influence the overall size and dimensions of themicropore array pattern. The scaling factor can be adjusted so that theedges of the outermost micropores are within a desired distance of theouter edge of the microporation. Additionally, the scaling factor can beadjusted so that the inner edges of the innermost micropores are withina desired distance of the inner edge of the microporation. Duality canbe generalized to n-dimensional space and dual polytopes; in twodimension these are called dual polygons, or three dimensions or aplurality of dimensions containing vertices, array's, or likewisecontaining tessalations both isotropic or anisotropic.

Distance Between Nearest Adjacent Micropores:

Along with consideration for the number and size of the micropores, thedistance between the centers of the nearest adjacent micropores can bedetermined. The distance between the centers of any two micropores maybe a function of the other array design considerations. In someembodiments, the shortest distance between the center of any twomicropores is never repeated (i.e., the pore-to-pore spacing is neverthe same exact distance). This type of spacing is also an example ofcontrolled asymmetry. In some other embodiments, the shortest distancebetween the center of any two micropores is always repeated (i.e., thepore-to-pore spacing is always the same exact distance). This type ofspacing is also an example of controlled symmetry. In some embodiments,the distance between two micropores are randomly arranged (i.e. thepore-to pore spacing is random). The system thus can provide controlledasymmetry which is at least partial rotational asymmetry about thecenter of the array design or pattern, random asymmetry which is atleast partial rotational random about the center of the array design orpattern, and controlled symmetry which is at least partial rotationalabout the center of the array design or pattern, and random symmetrywhich is at least partial rotational random about the center of thearray design or pattern.

In some embodiments, the rotational asymmetry may extend to at least 51%of the micropores of the pattern design. In some embodiments, therotational asymmetry may extend to at least 20 micropores of the arraypattern design. In some embodiments, the rotational symmetry may extendto at least 51% of the micropores of the pattern design. In someembodiments, the rotational symmetry may extend to at least 20micropores of the pattern design. In some embodiments, the rotationalrandom pattern may extend to at least 51% of the micropores of thepattern design. In some embodiments, rotational random pattern mayextend to at least 20 micropores of the pattern design.

In some embodiments, the 51% of the aperture pattern may be described inpolar co-ordinates by the Vogel model equation: φ=n*α, r=c√n, asdescribed above.

Co-Operative Eye Contact Lens/Eye Mask

The co-operative Eye contact lens/Eye mask (see FIG. 27A, element 2700,and FIG. 40) can be flexible or rigid, soft or hard. It can be made ofany number of various materials including those conventionally used ascontact lens or eye masks such as polymers both hydrophilic, hydrophobicor soft gel or collagen or dissolvable materials or special metals. Anexemplary flexible lens/mask may include a pliable hydrophilic(“water-loving”) plastic.

In some embodiments, the described systems, methods and devices of thepresent disclosure may include method and apparatus for treatment ofsclera and neighboring ocular structures and fractional microporationand resurfacing, laser eye microporation for rejuvenation or restorationof physiological eye function, and/or alleviation of dysfunction ordisease. In various embodiments, the arrays may take on a plurality ofgeometries, densities, configurations, distributions, densities and spotsizes and depths. They may also be preplanned and performed in varioustime points. It can also penetrate the epi sclera, sclera substantia, orlamina fusca at any percentage of required poration. Electromagneticenergy applications are may also be suitable.

Hydrophobic Scleral Lens Customizable Wafer, Nano, Pm Etc.: In Variousembodiments, a hydrophobic scleral lens customizable wafer can havevariable sizes measured generally in millimeters, micrometers ornanometers.

Generally, it is a scleral contact lens that can contain a computergenerated customized algorithm for a laser treatment on a patient'ssclera. First, spots can be registered that are retreatable and thespots can be profiled via the mask or lens. The mask can be made ofvarious materials including one or more hydrophobic polymers or blendsof polymers that are impenetrable by the laser. This can provide anadded level of protection for the surrounding tissue that is not goingto be treated in addition to smart mapping technology. A corneal centralcontact lens can be tinted to protect the cornea from the microscopelight and from the laser beam itself. In various embodiments, it can bedisposable and not reusable once the pattern is on the eye.Additionally, it can be delivered prepackaged sterilized containers.

This can be created by measuring biometry, morphology, anatomy,topography, keratotomy, scleral thickness, material properties,refractions, light scatter, and other features and qualities that may beimported, uploaded or otherwise inputted into a three dimensional (3D)dynamic FEM module which may be a platform for “Virtual Eye.” The systemof the disclosure may process the information of both cornea and lensand may run a plurality of algorithmic tests once all of the optics andinformation have been inputted. The system may apply mathematical andphysical scenarios aimed at enhancing accommodative power throughmanipulation of the scleral, and it may also give desirable Zernikeprofiling of the cornea which would produce maximum accommodative powerin the event that there are Laser Vision Correction (LVC) plusaccommodated planning. Once complete the pattern may be generated, e.g.,by ISIS (a visualization and eye mapping software for analyzing andreproducing a visual mapping of the eye refractive status the cornealrefractive status, e.g., both the lens refractive status and the cornealrefractive status, or “dual optic”) through Virtual Eye and there is avisualization of said pattern. In some embodiments, ISIS may be aservomechanism.

The wafer may also stamp coordinates at the 12 and 6 o'clock meridiansfor orientation on the eye by a physician. The wafer may also stamp aunique and different coordinate at the 10/2/4/7 meridians for thetreatment quadrant orientation for the physician. The wafer/contact lensmay be produced by a corresponding 3D printer which is connected to themother board of ISIS. Once completed, the lens may be sterilized priorto putting on the patient's eyes.

In some exemplary operations, initially, a laser that can be coupledwith or contain an eye tracker in some embodiments may be calibrated orinitiated and a lens is put in place by the physician. The wafer may actas both a mask and guide for the laser.

Still in FIG. 18, the lens design is called “semiscleral-contact” (SEQ).This lens has as its starting point, a bearing edge of the sclera at thecorneal 2.0 mm part consists of three curves. The SEQ lens features 10fenestrations, which prevents the lens getting stuck. Irregular cornealsurfaces can be corrected using RGP contact lenses, corneal lensesranging in diameter from 8.0 mm to 12.0 mm. Sclera lenses may vary indiameter from 22.0 mm to 25.0 mm.

To build up the lens and final fitting, formulas may be used for thecalculation and production of the lens. To narrow the whole range, itmay begin with a sagitta fitting set of 2.70 mm extending to 4.10 mm.Differences in the fitting set are similar to a fitting set for RGPlenses with a different radius of 0.05 mm between a normal step.

The SEQ fitting set expires with sagittal 0.1 mm height difference.Despite the DK value of 90, and 10 times fenestration of SEQ lens, anoxygen supply problem may persist. Lenses adjusted in diameters largerthan 12.0 mm have a lot of support that it is not moving and thus notear exchange can occur.

In some exemplary operations, 1) as the laser contains an eye tracker,the lens is put in place by a physician. The wafer acts as both a maskand guide for the laser. 2) This wafer guided system is unique to thelaser; the pattern is placed on the eye and through the lens itselfwhich is perforated during the process creating a map receipt of theprocedure and registering all spots by the scanner before and after thetreatment. 3) ISIS retains this information for this specific patient'seye, 4) In the event that a retreatment is needed. All information(topo, etc.) is imported back into the patient's profile for ISIS torecalculate and reconfigure ‘around’ the existing spots for furthermaximization. 5) ISIS calculates COP before and predictable COP afterapplying the simulation which can inform the patient and surgeon of theamount of COP possible for any particular patient with and withoutadditional LVC. 6) ISIS also demonstrates through use of the FEM virtualeye both the biomechanical functions, optical functions, as well as avision simulation at all distances. 7) ISIS also demonstrates a post opCOP, AA, Refractions, Zernike profile changes etc. and on the back endcontinues to capture all database information to come up with futuremore sophisticated and optimizing algorithms. 8) ISIS can also profilevarious algorithms to enhance the understand of the dual optic systemand give changing scenarios based on change of scleral thickness andother biometry, geometry, optics etc. with age. The usefulness of thisis infinite but a specific embodiment is that ISIS can generate anage-related treatment map from the patient's initial exam throughcataract age. Therefore, ISIS can predict how many spots and whatpattern should be used in advance so that the retreatment potentialareas will be ‘predetermined’ by ISIS upon the first wafer. This meansthat on subsequent visits, ISIS can alert the physician when there is acritical loss of COP and retreatment can start at any time (this wouldbe determined by the physician, patient and ISIS output). 9) ISIS mayalso have an audible interaction and can also alert the physician duringtreatment if there is a need for intervention, when it is complete andguide the physician at what exams should be evaluated for accuracy orfor more attention. ISIS can make recommendations to the physician, butthe physician is in control of the selection of programs ISIS willperform 10) ISIS also has a reference list and can search for papers,knowledge and recent trends as well. 11) ISIS may work like a voiceassistant, e.g., Apple Siri.

Laser features for some embodiments may include an Er:YAG OphthalmicLaser Lasing Medium, an Er:YAG laser with 2.94 μm wavelength; Pulseduration approximately 250 μsec; Rep rate may be 3, 10, 15, 20, 25, 30,40, 50 pps.

Various net absorption curves of various tissue components can beimportant. At 2.94 μm, wavelength laser can be the closest wavelength inthe near infrared spectrum to the peak absorption of H₂O 3.00 μm. Thisallows it to effectively evaporate H₂O from the tissue (ablationmechanism) with little thermal effect. Laser Tissue Interaction @ 2.94μm: 2.94 μm may be a great wavelength for tissue ablation; 10-20× betterabsorbed by water than CO2 at 10.6 μm; 3× better absorbed by water thanEr:YSGG at 2.79 μm; Ablation threshold for water at 2.94 μm about 1J/cm². The ablation occurs instantly and may be a surface effect only.This provides very precise ablation with little collateral tissuedamage.

Applications for Er:YAG ophthalmic systems can include a broad 510K forexcision, incision, evaporization of ocular soft tissue thereforeexpansion of use is inevitable after it is adopted including in:Ptyerigium surgery; glaucoma surgery; ocular nerve head entrapment(posterior sclera); intra ocular capsulotomy; extra ocular soft tissuesurgery; AMD; and others.

Methods and apparatuses for treatment of sclera and neighboring ocularstructures and fractional microporation and resurfacing are alsocontemplated.

As described herein, a system and method for performing fractionalresurfacing of a target area of an eye, e.g., the sclera, usingelectromagnetic radiation are provided. An electromagnetic radiation isgenerated by an electromagnetic radiation source. The electromagneticradiation is caused to be applied to a particular portion of a targetarea of eye preferably the sclera. The electromagnetic radiation can beimpeded from affecting another portion of the target area of the eye bya mask or scleral lens. Alternatively, the electromagnetic radiation maybe applied to portions of the target area of the sclera other than theparticular portion.

Additionally, described herein is a method for modifying tissue with aquasi-continuous laser beam to change the optical properties of the eyecomprises controllably setting the volumetric power density of the beamand selecting a desired wavelength for the beam. Tissue modification maybe accomplished by focusing the beam at a preselected start point in thetissue and moving the beam's focal point in a predetermined mannerrelative to the start point throughout a specified volume of the tissueor along a specified path in the tissue. Depending on the selectedvolumetric power density, the tissue on which the focal point isincident can be modified either by photoablation or by a change in thetissue's visco-elastic properties.

Ophthalmic Laser System

In various embodiments, an ophthalmic laser system of the presentdisclosure may include a laser beam delivery system and an eye trackerresponsive to movement of the eye operable with the laser beam deliverysystem for ablating scleral material of the eye both anterior and/orposterior through placement of laser beam shot on a selected area of thesclera of the eye. The shots are fired in a sequence and pattern suchthat no laser shots are fired at consecutive locations and noconsecutive shots overlap. The pattern is moved in response to themovement of the eye. Since the sclera of the eye is ‘off axis’ thescanning mechanism is novel in that it does not operate by fixation ofthe beam over the visual axis of the eye. Referring to FIG. 20 and FIGS.20A to 20D, rather the ‘off axis’ scanning mechanism may require an eyedocking system 2000 utilizing goniometric mirror or guidance system toablate opposing quadrants of the sclera outside the visual axis. Aclosed loop feedback system is in place internally to the scanner andalso between the eye docking system in and the scanner in the form of amagnetic sensor mechanism which both locks the laser head to the eyedocking system and by virtue of biofeedback positioning of the eye totrigger both eye tracking and beam delivery.

In some embodiments, the laser apparatus for rejuvenating a surface mayinclude means to select and control the shape and size of the areairradiated by each pulse of laser energy without varying the energydensity of the beam. By varying the size of the irradiated area betweenpulses, some regions of the surface may be eroded more than others andso the surface may be reprofiled. The method and apparatus are suitable,inter alia, for removing corneal ulcers and reprofiling the cornea toremove refractive errors and also for reprofiling optical elements. Inone embodiment, the beam from the laser enters an optical system housedin an articulated arm and terminating in an eyepiece having a suctioncup for attachment to an eye. The optical system may include a beamforming arrangement to correct an asymmetric beam cross-section, a firstrelay telescope, a beam dimensional control system and a second relaytelescope. The beam dimension control system may have a stop with ashaped window or a shaped stop portion and movable axially along aconverging or diverging beam portion. An alternative beam dimensioncontrol system has a stop with a shaped window and positioned betweencoupled zoom systems. Mirrors, adjustable slits and refractive systemsmay also be used. The laser can preferably be an Er:YAG laser in someembodiments. The apparatus may include a measurement device to measurethe surface profile, and a feedback control system to control the laseroperation in accordance with the measured and desired profiles.

In some embodiments, the method, apparatus, and system fortemplate-controlled precision laser interventions described hereinimproves the accuracy speed range, reliability, versatility, safety, andefficacy of interventions such as laser microsurgery, particularlyophthalmic surgery including ability to perform such laser surgeryoutside of the visual axis. Turning back to FIG. 19, FIG. 19 illustratesan exemplary diagram of instrument and system 1900 which are applicableto those specialties wherein the positioning accuracy of the lasertreatment is critical, wherever accurate containment of the spatialextent of the laser treatment is desirable, and/or whenever preciseoperations on a target or series of targets subject to the movementduring the procedure are to be affected. The system 1900 thus mayinclude the following key components: 1) a user interface, consisting ofa video display, microprocessor and controls, gui interface, 2) animaging system, which may include a surgical video microscope with zoomcapability, 3) an automated 3D target acquisition and tracking systemthat can follow the movements of the subject issue, for example and eye,during the operation, thus allowing the surgeon user to predetermine hisfiring pattern based on an image which is automatically stabilized overtime, 4) a laser, with which can be focused so that only the precisetreatments described by the user interface are affected, 5) a diagnosticsystem incorporating a mapping and topography, numerical data,mathematical data, geometrical data, imaging data, by means formeasuring precise surface and 3D shapes prior to, during and subsequentto a procedure, said measurements to be executed online within timescales not limited to human response times, and can be real time, and 6)fast reliable safety means, whereby the laser firing is interruptedautomatically, should any conditions arise to warrant such interruptionof the procedure for example a safety concern.

FIGS. 20(E-H) illustrate further the off-axis features of the lasersystem. In some embodiments, the system may provide 360-degree scanning.In some embodiments, the laser delivery may be nominally positionedperpendicular to the surface of the eye for treatment. The rotationalsymmetry axis is the eye fixation point. Treatment areas for the laserpreferably are not hidden by eye lids and other features of the patient.Eye fixation axis and the laser beam axis have a fixed angle to exposepores in defined zones. The laser beam delivery can be rotated aroundthe eye, β. In some embodiments, key elements may include: laser beamand scan (e.g., OCT) area are on same centerline, and scan area andfocal length is matched to laser spot size and focal length. Camera islocated just off laser centerline. Zoom ability is provided to seeentire eye or see bottom of pore. Image provides features for eyetracking system to lock on, off axis. Color image can be provided inorder to sense depth by tissue coloration. Eye fixation point is fixedangular relationship to the laser delivery beam 180° from the laserdelivery beam around (3. FIGS. 20G to 20I illustrate different exemplarytypes of off axis scanning.

Referring to FIG. 20I, another exemplary off-axis scanning, according tosome embodiments of the present disclosure, is illustrated. As shown,the treatment may be angular.

In some embodiments, the system for use in ophthalmic diagnosis andanalysis and for support of ophthalmic surgery may include 3D-7D mappingmeans for sensing locations, shapes and features on and in a patient'seye in three dimensions, and for generating data and signalsrepresenting such locations, shapes and features, display meansreceiving signals from the 3D-7D mapping means, for presenting to a userimages representative of said locations, shapes and features of the eye,at targeted locations including display control means for enabling auser to select the target location and to display a cross section ofportions of the eye in real time both during ablation and after eachlaser pulse, position analysis means associated with and receivingsignals from the three dimensional mapping means, for recognizing theoccurrence of changes of position of features of the eye, targettracking means associated with the position analysis means, forsearching for a feature of target tissue and finding said features newposition after such a change of position, and for generating a signalindicative of the new position, and tracking positioning means forreceiving said signal from the target tracking means and for executing achange in the aim of the three dimensional mapping means to the newposition of said feature of the target tissue, to thereby follow thefeature and stabilize the images on the display means.

The display means can be a video display, and further including surgicalmicroscope or digital monitor or smart device means directed at thepatient's eye, for taking video microscopic images real time of targetareas of the ocular tissue and for feeding video image information tothe video display means to cause such video microscopic images to bedisplayed, assisting the user in diagnosis and analysis enabling displayof different cross sections of the patient's tissue as selected by theuser in real time.

The tracking positioning means may include a turning mirror underautomatic control, robotic control, blue tooth control and the systemmay include an objective lens assembly associated with the mapping meansand having a final focusing lens, with the turning mirror positionedwithin the objective lens assembly and movable with respect to the finalfocusing lens is an embodiment.

In some embodiments, the system may include a laser pulsed source forproducing an infrared to near infrared light laser beam having a powercapable of effecting a desired type of surgery in an eye, laser firingcontrol means for enabling a surgeon/user to control the aim, depth, andtiming of the firing of the laser to effect the desired surgery, 3D-7Dmapping means directed at a patient's eye, for obtaining datarepresenting the location and shapes of features on and inside the eye,microprocessor means for receiving data from the three dimensionalmapping means and for converting the data to a format presentable on ascreen and useful to the surgeon/user in precisely locating features ofthe eye and the aim and depth of the laser beam within those features,and display means for displaying microprocessor-generated imagesrepresenting the topography of the eye and the aim and depth of thelaser beam before the next pulse of the laser is fired to thesurgeon/user in preparation for and during surgery, with display controlmeans for enabling the surgeon/user to select areas of the eye fordisplay, including images of cross sections of portions of the eye.

The infrared or near infrared pulsed, free running, or continuous orQ-Switched light laser power source may generate a laser beam capable ofeffecting the desired laser surgery in the patient's tissue, includingwithin transparent tissue of the patient. The system may include anoptical path means for receiving the laser beam and redirecting thelaser beam and focusing it as appropriate toward a desired target in thetissue to be operated upon.

The system may include a laser housing positioned to intercept anddirect the optical path means, for taking images of said target alongthe optical path means and for feeding video image information to thevideo display means, and tracking for tracking movements of the subjecttissue at which the system is targeted without damaging the subjecttissue before the next pulse of the laser is fired and shifting theoptical path accordingly before the next pulse of the laser is fired,such that information and images generated by the three dimensionalmapping means and by the surgical microscope means, as well as theaiming and position of the laser beam, following changes in position ofthe tissue. Each image frame taken, and information is sent to the videodisplay after each firing inside the 3D-7D micropore before and afterthe firing of the laser in dynamic real time and surface view. GUI mayinclude integrated multiview system in 7 directionalities for imagecapture including: surface, internal pore, external pore, bottom of themicropore, whole globe eye view, target array area.

In some embodiments, 7 cube may be the preferred projection for themicroprocessor: but other examples exist in dimensional sphere shape,space, and may be integrated into the GUI and microprocessor. Orthogonalprojections can include examples shown in FIG. 8 above.

The system may include multi-dimensional scaling, linear discriminantanalysis and linear dimensionality reduction processing as well aslocally linear embedding and isometric maps (ISOMAP). Nonlineardimensionality reduction methods may also be included.

In some embodiments, the system can allow for a 1D, 2D, 3D, or 4D, andup to 7D conversion of the topological images or fibrations. Thefibration is a generalization of the notion of a fiber bundle. A fiberbundle makes precise the idea of one topological space, called a fiber,being “parameterized” by another topological space, called a base. Afibration is like a fiber bundle, except that the fibers need not be thesame space, nor homeomorphic; rather, they are just homotopy equivalent.Where the fibrations is equivalent to the technical properties of thetopological space in 3, 4, 5, 6, and 7 dimensional sphere spaces acontinuous mapping p:E→B satisfying the homotopy lifting property withrespect to any space. Fiber bundles (over paracompact bases) constituteimportant examples. In homotopy theory, any mapping is ‘as good as’ afibration—i.e. any map can be decomposed as a homotopy equivalence intoa “mapping path space” followed by a fibration into homotopy fibers.

A laser workstation may be equipped with three programmable axes (X, Y,Z; can be expanded to 5 axes) has an automatic rotary table machine,programmable X, Y, Z-axis and a 2-station rotary table. It can include aHuman Machine Interface (HMI) with Security user access level,diagnostic and data logging for validated processes and user friendlyoperation, as well as a sorter module adaptable for unique pulsemodulation, where: hole diameter: 0.1 μm-1000 μm; drill depth max. 0.1μm-2000 μm; Hole tolerances: >±1-20 μm

Operational features can also include networked computer connection,iPad operations, joy stick operations, touch screen operations, iPhoneoperations, remote or Bluetooth operations, digital camera integratedoperations, video integrated operations, and others.

System and Methods for Laser Assisted Ocular Drug Delivery

FIG. 20J illustrates the aqueous flow within the eye. Aqueous outflowcan be regulated by active contraction of the ciliary muscle andtrabecular cells. Contraction of the ciliary muscle expands thetrabecular meshwork and increases outflow and decreases IOP. Contractionof trabecular cells decreases outflow and increases IOP. In someembodiments, the described systems would cause improvement in ciliarymuscle dynamics would improve hydrodynamics of aqueous drainage.

The uveoscleral pathway is an alternative pathway for aqueous drainagethat may account for 10-30% of all aqueous outflow. For the uveoscleralpathway, aqueous enters the ciliary body and passes between ciliarymuscle fibres into supra-ciliary and suprachoroidal spaces. FIGS. 20Kand 20L illustrate how in some embodiments the described systems wouldincrease uveal outflow.

The sclera is 10 times more permeable than the cornea and half aspermeable as the conjunctiva. Hence permeants can diffuse and enter theposterior segment via the transcleral route. With traditional drugdelivery (such as eye drops), approximately 90% of drug is lost due tonasal lacrimal drainage, tear dilution and tear turnover leading to poorocular bioavailability, and less than 5% of the topical drug everreaches the aqueous humor.

In some embodiments, the described systems, methods and devices of thepresent disclosure may be used for laser assisted ocular drug delivery,such as methods and apparatuses for phototherapeutically treating, e.g.by ablating, coagulating, and/or phototherapeutically modulating atarget tissue, e.g., scleral tissue and other intraocular tissues suchas choroid, subchoroidal space, neuroretina, or others. There isdisclosed a method for creating an initial permeation surface (A) in abiological membrane (1) comprising: a) creating a plurality ofindividual micropores (2 i) in the biological membrane (1), eachindividual micropore (2 i) having an individual permeation surface (2i); and b) creating such a number of individual micropores (2 i) and ofsuch shapes, that the initial permeation surface (A), which is the sumof the individual permeation surfaces (2 i) of all individual micropores(2 i), having a desired value. A microporator performing the method isalso disclosed. Biological surface may be an eye in this case. In thecase of the eye: irradiating the area of the sclera such that thetherapeutic agent passes through the open area created by the laserradiation and is thereby delivered to intraocular target tissues in theanterior or posterior globe such as the choroid, neuroretina, retinalepithelium, uvea, vitreous, or aqueous.

In some embodiments, the described systems, methods and devices of thepresent disclosure may be used for laser assisted ocular drug delivery,such as methods and apparatuses for a smart activated polymer carrier,which could be light activated, light modified poly(acrylamide)s, orcould be used to finely manipulate the pore size of nano/microporousmaterials and demonstrate its application for reversible color tuning ofporous polymer photonic crystals based on humidity condensation.

Additionally, in some embodiments, the systems described herein caninclude one or more of: an eye docking station, a scleral mask/nozzleguard, nozzle, novel 360dg jointed articulated arm, novel off axisscanning, drug delivery system, depth control, accessories, Fibonaccialgorithms, and others. Some options may include hand held wands,fiberoptic hand pieces, scanning automated laser applicator,workstation, remote control over wireless communication, e.g., Bluetoothor others, hand held tonometer for preoperative and post-operativeocular pressure measurements, and others.

FIG. 20M illustrates an exemplary hand piece delivery system vs.articulated arm.

For delivery purposes, the eye can be considered as consisting of twosegments. The anterior segment comprises the cornea, conjunctiva, scleraand anterior uvea while the posterior segment includes the retina,vitreous and choroid. There may be three main routes for delivery ofdrugs to the eye: topical, systemic, and intra-ocular injection.Controlled delivery systems, such as ocular inserts, minitablets anddisposable lenses, can be applied to the exterior surface of the eye fortreatment of conditions affecting the anterior segment of the eye.Extended residence times following topical application have thepotential to improve bioavailability of the administered drug andadditionally a range of strategies has been tested to improvepenetration including cyclodextrins, liposomes and nanoparticles. Drugdelivery strategies for treatment of diseases of the posterior segmentof the eye will be discussed herein. The development of therapeuticagents that require repeated, long-term administration is a driver forthe development of sustained-release drug delivery systems to result inless frequent dosing and less invasive techniques.

Drug delivery to the eye is often for two main purposes. First, to treatthe exterior of the eye for periocular conditions such asconjunctivitis, blepharitis and dry eye and secondly to treatintraocular disorders such as glaucoma, diabetic retinopathy, uveitisand age-related macular degeneration (AMD), retinal pathologies, andbiomechanical compression, restriction, or interference with normalphysiological functions of vessels, nerves, or connective tissues underthe surface of the eye tissue. Under normal conditions drugs that areadministered to the eye as aqueous eye drop solutions will rapidly bediluted and washed from the eye surface by the constant flow of tearfluid. Drug dilution on the eye surface also reduces drug flow from thesurface into the eye. Consequently, eye drops must be administeredfrequently and at high concentrations in order to achieve therapeuticlevels. The successful delivery of lipophilic drugs in aqueous eye dropsuspensions has led to the development of delivery systems intended toincrease the residence times of drug on the surface of the eye. Bymaintaining high levels of drug within the tear fluid for extended timesit may be possible to increase uptake into the eye. This can also becombined with strategies to improve ocular penetration. Beyond the useof conventional systems such as solutions, suspensions, creams and gels,developments have been made using devices such as inserts andviscoelastic solutions.

In some embodiments, the described systems, methods and devices of thepresent disclosure may be used for posterior ocular drug delivery in theposterior sclera including but not limited to the peripapillary scleraand lamina cribrosa. Currently, treatment of diseases in the posteriorglobe is hampered by poor efficacy of topical drugs and that there is nominimally invasive way to reach or to treat the posterior globe.

FIGS. 20N and 20O illustrate in some embodiments the treatment zones inthe anterior and posterior globe, according to some embodiments of thepresent disclosure.

In some embodiments, the described systems, methods and devices of thepresent disclosure may be used for, but not limited to, the delivery ofdrugs, nutraceuticals, grape seed extract, stem cells, plasma richproteins, light activated smart polymer carriers, and matrixmetalloproteinases. FIGS. 20P-1 to 20P-3 illustrate, in someembodiments, the exemplary targets for choroid plexus drug andnutraceutical delivery.

It is often difficult to attain and retain effective drug concentrationsat the site of action. Only about 5% of the applied dose from eye dropspenetrates the cornea to reach the ocular tissues and residence timesare around 2-5 minutes. Attempts to improve ocular bioavailabilityinclude extending drug residence time in the conjunctival sac andimproving drug penetration across the cornea, the major pathway of drugentry into the internal eye. Delivery systems for topical administrationinclude suspensions, gels, erodible and non-erodible inserts and rods.

Increasing the viscosity of topical formulations can improve retentionin the eye and combinations of viscosity-modifying agents may provesynergistic. Such formulations are particularly useful as artificialtears and ocular lubricants but may also be utilized for the topicaldelivery of drugs to the eye. Polyvinyl alcohol (PVA) and cellulosessuch as hydroxypropyl and methylcellulose are often used as viscositymodifiers as they have a wide range of molecular weights and demonstratecompatibility with many of the topically applied active agents. Specificcombinations of polymers can be selected to obtain specific viscosity orgelling characteristics. In situ gelling systems undergo a transitionfrom a liquid phase to a solid phase forming a viscoelastic gel inresponse to a trigger such as change in pH, temperature of the presenceof ions. Poloxamers, block copolymers of poly(oxyethylene) andpoly(oxypropylene) form thermoreversible gels in the 25-35° C. range andare generally well tolerated. Cellulose acetate phthalate (CAP)undergoes a phase transition triggered by change in pH. Such systemshowever require high polymer concentrations, which can result indiscomfort to the user. Gellan gum is an anionic polysaccharide whichforms a clear gel in the presence of mono or divalent cations. Once itis gelled the first controlled release ophthalmic delivery device waslaunched in the mid-1970s. It comprises the active pilocarpine andalginic acid contained within a reservoir enclosed by tworelease-controlling membranes made of ethylene-vinyl acetate copolymerand enclosed by a white retaining, Like liposomes, polymericmicroparticulate delivery systems such as microspheres and nanosphereshave been investigated for topical delivery to the eye. Particles in themicrometer size range are termed microspheres whereas nanoparticles aresub-micron in diameter. FIGS. 20Q-1 to 20Q-3 illustrate how in someembodiments the described systems of the present disclosure may be usedfor transcleral drug delivery and to improve drug intracellular releaseand penetration. They can be manufactured using a number of techniquesincluding milling and homogenization, spray-drying, supercritical fluidtechnology and emulsion solvent evaporation. Incorporation ofmicroparticles into viscous drops and gels would facilitate easieradministration than aqueous suspension formulations. Microporationmethod may enable active drug to penetrate the sclera and reach thetargeted underlying tissue. The delivery system may use synergisticmechanism to enhance penetration. Thermodynamic stable properties mayallow solubilization of drug and then promote release of drug. Methodsmay include intraocular drug delivery via scleral vessels and aqueous. Asmart activated polymer carrier may be incorporated, and may be lightactivated, light modified poly(acrylamide)s, or may be used to finelymanipulate the pore size of nano/microporous materials and demonstrateits application for reversible color tuning of porous polymer photoniccrystals based on humidity condensation.

As a result, although topical ocular and subconjunctival sites aretherefore used for anterior targets, intravitreal administration isdesirable for posterior targets. Local administration of the drug willdecrease the likelihood of side effects, particularly with potentmolecules with severe side effects such as immune-suppressants. Alone,or in combination, these can be useful for alleviating conditionsassociated with dry eye. Effective blood retinal barriers prevent mostsystemically administered drugs from achieving therapeutic levels in thevitreoretinal space and side effects experienced following systemicadministration of such potent molecules limit the usefulness of theroute Sustained release may prolong the duration of effectiveconcentration at the site of action as demonstrated by the currentdelivery systems. Controlled release formulations proposed for sustainedintravitreal delivery include liposomal formulations, biodegradablemicrospheres, biodegradable and non-biodegradable implants. Entrappingthe drug in a nanoparticle prior to incorporation into a contact lens isa strategy that can be used to sustain the release. Providing thenanoparticle size and loading are low, then the lens should remaintransparent. Particulate polymeric delivery can include microspheres ornanospheres that can be manufactured in a number of ways includingspray-drying, emulsification and solvent evaporation and precipitation.

Microspheres may be useful for delivery to the anterior segment, toadhere to the surface of the eye and prolong release but they are alsouseful as sustained release injectable formulations. FIG. 20Rillustrates an exemplary opthacoil, which may include a drug-loadedhydrogel embedded on a coiled wire designed to be placed in theconjunctival fornix. Following injection of nanoparticles into thevitreous, optional targeting of drug-loaded sustained releasemicrospheres within the eye has also been explored by modifying surfaceof particles to alter their distribution within the eye. FIG. 20Sillustrates, according to some embodiments, exemplary drug deliverycarriers. FIGS. 20T-1 to 20T-3 illustrate, according to some embodimentsof the present disclosure, a scleral wafer.

In some embodiments, the drug delivery system may include a drug and alens, disposed on an eye, having a back surface comprising: a centralportion (corneal) and a scleral portion having an outer rim and an innerrim and a treatment portion consisting of an outer rim, an inner roomand an interlocking carrier depot which has a plurality of tissue arraysizes, shapes and variations. Corneal portion may be made of siliciumcarbide to protect the cornea and or can be metallic. In someembodiments, silicium carbide may be preferred. It may also be opaque.The lens may be a scleral lens covering at least 18 mm in diameter. Insome embodiments, the scleral portion of the lens may contact only thesclera. The treatment portion of the lens may, in some embodiments,contact only the sclera and the periphery of the cornea including thecorneoscleral envelope and limbus.

In some embodiments, the haptic portion of the scleral lens may furtherdefine a channel that extends radially at least part of the distancebetween the outer rim and the inner rim. The drug may be selected fromthe group consisting of an antibiotic, an antiviral, an antifungal, anantiparasitic, a corticosteroid, a non-steroidal anti-inflammatory, amydriatic, cycloplegic, a biologic, a drug that modifiesneovascularization, a drug that increases aqueous outflow, a drug thatreduces aqueous secretion, an antihistamine, a secretagogue, a mast cellstabilizer, a tear supplement, an anti-metabolite, and animmunomodulatory, VEGF, and other posterior drugs such as timoline, etc.

In some embodiments, the treated disease may include bacterialinfection, viral infection, fungal infection, parasitic infection,inflammation, neovascularization, ocular surface disease, glaucoma,allergy, dry eye, dysplasia, neoplasm, and AMD.

In some embodiments, the treatment portion of the lens may be made ofmesoporous silica. Photoactivated moving parts based on thephotoisomerization of azobenzene derivatives have been used inconjunction with mesoporous silica. The back and forth wagging motionhas been demonstrated to act as a molecular impeller that regulates therelease of molecules from the pores of silica nanoparticles under“remote control” upon photoexcitation. Azobenzene-driven release, unlikethat regulated by many other nanomachines, can occur in aqueousenvironments. Using light-activated mesostructured silica (LAMS)nanoparticles, luminescent dyes and ocular drugs are only releasedinside of the target tissue array (e.g. sclera) that are illuminated atthe specific wavelengths that activate the impellers. The quantity ofmolecules released is governed by the light intensity and theirradiation time. The irradiated target tissue array is exposed tosuspensions of the particles and the particles are taken up by thecells. Cells containing the particles loaded with a particular drug arereleased from the particles inside of the cells only when the impellersare photoexcited by a particular wavelength. The ocular drug of choicewhich is loaded into and released from the particles inside the cellsunder light excitation, and apoptosis is induced. Intracellular releaseof molecules may be sensitively controlled by the light intensity,irradiation time, and wavelength, and the anticancer drug deliveryinside of cells is regulated under external control.

The drug delivery system may be used within thepreoperative/perioperative/postoperative state for any drug deliveryneeded for a plurality of eye surgeries for use prophylactically or postoperatively.

In some embodiments, the transcleral delivery system for treating an eyeof a patient may include an apparatus for facilitating transcleraldelivery of a drug through an area of the apparatus and may include anablator that is configured to generate a microporation in the area ofthe sclera of the eye of the patient, and may include a drug, whereinthe drug effects at least one of the biological regulation of the targettissue. The drug may be administered transclerally or intrasclerally toa site of laser poration having a predetermined permeation surface overtime, wherein the predetermined permeation surface over time iseffective to achieve a predetermined deposit concentration of the atleast one drug to thereby treat the eye disease, further wherein thesite of laser poration comprises a plurality of pores having differentgeometries. The drug may be transclerally or intrasclerally administeredat a first location, and a plurality of drugs may be transclerally orintrasclerally administered at a different location. The drug may alsobe administered into the suprachoroidal space. The drug may be deliveredeither after or during the irradiation of the target tissue array.

Turning back to FIGS. 20, 20A-20B, the system of the disclosure mayinclude an eye docking station 2000. The eye docking station 2000 may bepositioned above the eye 2010 during a medical operation. FIG. 20Cillustrates an exemplary top view of the eye docking station 2000. Theeye docking station 2000 may provide a view of the four quadrants. FIG.20D illustrates an exemplary scleral fixation component 2020 attachableto the eye docking station 2000.

In some embodiments, the laser docking station may include the femaleend to the laser housing unit can be accomplished using magnetic sensorsbetween the female and male parts which are in a closed feedback loopwith the laser head. These sensors will detect the spectral reflectionof the tissue which is differently absorbed by Er:YAG by the nature ofthe Er:YAG wavelength.

Turning to FIGS. 21A-21B, embodiments of a nozzle guard 2100 and 2110are illustrated. FIG. 22 illustrates, in some exemplary operations, thenozzle guard 2110 being attached to a nozzle 2200. FIG. 23 illustratesthe nozzle 2200 being fitted with disposable insert and filter 2310.

FIG. 24 illustrates and exemplary workstation 2400 of the lasermicroporation system of the present disclosure, and hand piece andrelated apparatus 2420 for laser surgery of the eye. The workstation2400 can include the method, apparatus and system fortemplate-controlled precision laser interventions as described above. Asdescribed above, the method, apparatus and system may improve theaccuracy, speed range, reliability, versatility, safety, and efficacy ofinterventions such as laser microsurgery, particularly ophthalmicsurgery including ability to perform such laser surgery outside of thevisual axis.

The workstation 2400 may can include GUI interface which is touch screenor remotely controlled. The graphical user interface (GUI), is a type ofuser interface that allows users to interact with electronic devicesthrough graphical icons and visual indicators such as secondarynotation, instead of text-based user interfaces, typed command labels ortext navigation.

The workstation 2400 may include an articulating arm 2410; a laserhousing unit 2500 (FIGS. 25A-25B) which may include: a CCD video camera;Galvos Scanner capable of off axis scanning; aiming beam; and others.

FIGS. 25A-25B illustrate an exemplary embodiment of the housing unit2500 which is rotatable 360 degrees.

The workstation may include three-dimensional mapping means, at leastone communicatively coupled microprocessor, power supply, and thedisplay means include means for presenting images to the surgeon/userindicating precise current location of laser aim and depth in computergenerated views which comprise generally a plan view and selected crosssectional views of the eye representing features of the eye at differentdepths.

The workstation may also include an optical path with a focusing lenscapable of controlling the focus of the laser beam on the eye tissue,and thus the depth at which the laser beam is effective, within about 5microns, with depth control means for the surgeon to vary the focus ofsaid lens to control the depth at which the laser beam is effective.

The workstation may further include system program means enabling thesurgeon/user to pre-program a pattern of lesions in the ocular tissuealong three axes in three dimensions and to activate the laser to followthe preselected pre-programmed path of surgery automatically.

The workstation user interface can include equipment for presentinginformation to a surgeon/user and for enabling control of the surgicalprocedure by the surgeon/user, including video display means forpresenting precise information, patterns and meridians of arrays to thesurgeon/user relating to the location in a patient's tissue at which thesystem is targeted, and the three-7-dimensional topography and contoursof features of the subject tissue including imaging of cross sections oftissues, scanning surfaces and areas and real time dynamic control ofthe firing of the surgical laser beam by the user.

The workstation may contain or include an imaging system connected tothe video display means, including three-dimensional toseven-dimensional mapping means for generating, reading, andinterpreting data to obtain information regarding the location in sevendimensions of significant features of the tissue to be operated upon,and including microprocessor means for interpreting the data andpresenting the data to the video display means in a format useful to thesurgeon/user, This also includes an anatomy locator and erasertechnology which has a chromophoric sensor to sense change in color,dimension, water content, shape, spectral properties, optical propertiesand has a reverse scanning biofeedback feature which can outline precise3D-7D imagery of blood vessels, veins, and any other untargeted anatomy.It is able to signal the laser to avoid this untargeted anatomy. Thereis also an eraser feature that the user/surgeon can manually identify onthe touch screen GUI interface to guide the laser to avoid erasedareas/arrays/spots/regions.

The laser workstation can be equipped with three programmable axes (X,Y, Z; can be expanded to 5 axes) has an automatic rotary table machine,programmable X, Y, Z-axis and a 2-station rotary table Includes a HumanMachine Interface (HMI) with Security user access level, diagnostic anddata logging for validated processes and user-friendly operation. Asorter module with adaptable operational features: unique pulsemodulation; hole diameter: −1 μm-800 μm; drill depth max. 0.1 μm-2000μm; Hole tolerances: >±0.1 μm-20 μm.

Depth Control

In most tissues, disease progression is accompanied by changes in themechanical properties. Laser speckle rheology (LSR) is a new techniquewe have developed to measure the mechanical properties of tissue. Byilluminating the sample with coherent laser light and calculating thespeckle intensity modulations from reflected laser speckle patterns, LSRcalculates τ, the decay time constant of intensity decorrelation whichis closely associated with tissue mechanical properties. The use of LSRtechnology can be validated by measuring mechanical properties oftissue. LSR measurements of τ are performed on a variety of phantom andtissue samples and compared with the complex shear modulus G*, measuredusing a rheometer. In all cases, strong correlation is observed betweenτ and G* (r=0.95, p<0.002). These results demonstrate the efficacy ofLSR as a non-invasive and non-contact technology for mechanicalevaluation of biological samples.

It is known that disease progression in major killers such as cancer andatherosclerosis, and several other debilitating disorders includingneurodegenerative disease and osteoarthritis, is accompanied by changesin tissue mechanical properties. Most available evidence on thesignificance of biomechanical properties in evaluation of disease can beobtained using conventional mechanical testing, ex vivo, which involvesstraining, stretching, or manipulating the sample. To address the needfor mechanical characterization in situ, a new optical tool can includean LSR.

When a turbid sample, such as tissue, is illuminated by a coherent laserbeam, rays interact with tissue particles and travel along paths ofdifferent lengths due to multiple scatterings. Self-interference of thereturning light creates a pattern of dark and bright spots, known aslaser speckle. Due to thermal Brownian motion of scattering particles,light paths can constantly change, and speckle pattern fluctuates withtime scales corresponding to the mechanical properties of the mediumsurrounding the scattering centers.

Open biofeedback loops can be used in various embodiments duringintraoperative procedures using chromophore and other biofeedbackprocesses. In chromophore embodiments, saturation of color can bemeasured with sensitivity to micron levels of accuracy to determinecorrect and incorrect tissues for surgical procedures. Pulse decisionscan be made based on various preset color saturation levels. This is incontrast to current systems that may use color or other metrics only forfeedback to imaging equipment and not to actual laser applicationdevices that are applying treatments. Similarly, subsurface anatomyavoidance for predictive depth calibration can use tools to determinedepth calculation in real-time to determine how close extraction orother treatment procedures are to completion, while also maintainingactive monitoring for undesirable and unforeseen anatomical structures.As such, hydro- or other feature monitoring is different from oldersystems that may monitor surface levels for reflection but are unable toeffectively measure depth in a tissue or other biological substance.

LSR exploits this concept and analyses the intensity decorrelation ofbackscattered rays to produce an estimate of tissue biomechanics. Tothis end, LSR calculates the intensity decorrelation function of speckleseries, g₂(t), and extracts its decay time constant, τ, as a measure ofbiomechanical properties.

Laser Speckle Rheology Bench

In some exemplary operations, bulk mechanical properties of tissue andsubstrates are measured using a bench-top LSR set-up. This set-upincludes a laser of a plurality of coherence laser lengths followed by alinear polarizer and a beam expander. A focal length lens and a planemirror are used to focus the illumination spot at the target tissuesite. Laser speckle patterns are imaged using a high-speed CMOS camera.The image series are processed and the correlation between each twoframes is calculated to determine the intensity decorrelation function,g₂(t). Temporal and spatial averaging is applied over the image seriespixels to reduce statistical errors. A single exponential is fitted tothe resulting g₂(t) curve to extract the time constant, τ.

The sclera is a viscoelastic tissue and its complex shear modulus can beadjusted accurately by reshaping with a laser or selective fibril and/ormicrofibril ablation thereby modifying viscoelastic modulus and reducingbiomechanical stiffness. Measurement of mechanical properties throughbiofeedback loop during the course of the laser procedure enablesevaluation of LSR sensitivity to small gradual changes in mechanicalproperties and therefore tittering of the desired effect. Moreover, anaspect of some embodiments of the present disclosure is the simulationthrough FEM (VESA) of changes in viscoelastic modulus through artificialintelligence algorithm predictions of desired patterns of reshapingand/or fibril/microfibril selective ablations.

The scleral transparency or changes in opacity/transparency can createscattering features. The final volume fraction is measured tosufficiently identify strong back-scattered signal. LSR measurements areobtained followed by a conventional mechanical frequency sweep for aspecified duration time. A final time point measurement is performed ontreated sclera using both LSR and AR-G2 instrument.

As used herein, chromophore relates to water absorption spectrum toquantify tissue chromophore concentration changes in near-infraredspectroscopy.

Systems and methods herein can be used for measuring the differentialpath length of photons in a scattering medium utilizing the spectralabsorption features of water. Determination of this differential pathlength is a prerequisite for quantifying chromophore concentrationchanges measured by near-infrared spectroscopy (NIRS). Thequantification of tissue chromophore concentration measurements is usedto quantify depth of ablation rates yielded by water absorption andtime-resolved measurements through various layers of scleral tissue asit relates to ablation rate of absorption, pulse width and energy of thelaser beam.

The number of pulses can be detected by the laser as well as a videocamera, e.g., a CDD camera, which can detect reflect light which isreflected differently through different colors.

In some embodiments, water can also be used as a chromophore since thesclera is made 99% of water, therefore pulses per pore lasered inscleral tissue can be feedback to the laser system and can be utilizedby how many pulses per pore and at which tissue level it is at sincethere is tissue hierarchy in the sclera.

In some embodiments, electrical vibrations can provide biofeedback. Thequantification of tissue chromophore concentration measurements may beperformed through the galvos or optics comparing the differential pathestimates yielded by water absorption and time-resolved measurements,pulses per pore. The sensor is also able to deliver and quantify thedynamic changes in the absorption coefficient of water as a function ofincident fluence at 2.94 μm.

Chromophore concentrations, absorption and scattering properties ofhuman in vivo sclera absorption and reduced scattering coefficients ofin-vivo human connective tissue such as the sclera of the eye canprovide critical information on non-invasive connective tissue (sclera)diagnoses for surgical and clinical purposes. To date, very few, if any,in-vivo scleral optical properties have been reported. As statedpreviously, absorption and scattering properties of in-vivo skin in thewavelength range from 650 to 1000 nm using the diffusing probe in the“modified two-layer geometry.” As disclosed herein, determination of thespectra of scleral optical properties may be done continuously in therange from 500 to 1000 nm. It was found that the concentration ofchromophores, such as oxy-hemoglobin, deoxy-hemoglobin, and melanin,calculated based on the absorption spectra of eighteen subjects atwavelengths above and below 600 nm were distinct because of the inherentdifference in the interrogation region. The scattering power, which isrelated to the average scatterer's size, demonstrates a clear contrastbetween scleral phototypes, scleral sites, and wavelengths. The presentdisclosure may use the concentrations of oxy- and deoxy-hemoglobinassessed at wavelengths above and below 600 nm to distinguish betweentargeted tissue (sclera) and adjacent anatomy (arteries/veins). Forexample, the sclera is not vascularized and would demonstrate adeoxy-hemoglobin response while the adjacent blood vessel woulddemonstrate an osy-hemoglobin response. The diffuse reflectancetechniques with the visible and near infrared light sources can beemployed to investigate the hemodynamics and optical properties of upperdermis and lower dermis.

The absorption coefficient μa, the scattering coefficient μ_(s)′, andchromophore concentrations of sclera are fundamental properties oftissue that can provide essential information for many surgical,therapeutic, and diagnostic applications such as monitoring of skinblood oxygenation, melanin concentration, detection of hydration withfluorescence, laser surgery, and photodynamic therapy.

Photon diffusion theory derived from the radiative transport equation isusually employed as a forward model to determine optical properties ofin-vivo samples at source-detector separation longer than fivemean-free-paths, where mean-free-path is defined as 1/(μ_(a)+μ_(s)′).This has been proven to be a not adequate model for source-detectorseparations longer than five mean-free-paths, because boundaryconditions and the assumption of multiple scattering in a turbid mediumcannot be satisfied. In order to limit interrogation to superficialtissue volumes, such as sclera, source-detector separations shorter thanfive mean-free-paths may be incorporated. In-vivo techniques can employalternative forward models to determine optical properties of sclera. Todetermine optical properties of in-vivo sclera the present disclosuremay use visible reflectance spectroscopy with a multi-layer scleralmodel and an optimization algorithm predetermined by use of video cameraguidance, e.g., OCT, UBM or CCD video camera guidance integrated usingartificial intelligence FEM. A multi-layer skin model and a number offitting parameters, such as layer thickness, chromophores, andscattering properties for each layer, and their corresponding rangesmust be chosen carefully in advance to avoid non-uniqueness in thesolution space.

A system model may be employed to extract optical properties fromdiffuse reflectance spectra collected from sclera in-vivo. The techniquemay require that all of the chromophores contributing to the measuredsignals are known in advance and the reduced scattering coefficient hasa linear relation to the wavelength in order to separate absorption andreduced scattering coefficients from measured reflectance. Allconstituent chromophores are then determined, and the absorption spectrais recovered. In addition, the reduced scattering coefficient produces alinear dependence on wavelength and the empirical mathematical modelwill recover tissue optical properties properly.

Further embodiments herein may include the use of a probe design whichhas been adjusted into multiple source-detector pairs so that it canemploy a white light source to obtain continuous spectra of absorptionand reduced scattering coefficients. The advantages of thismulti-source-detector separation probe include relative low instrumentcost and self-calibration in real time in vivo for instrument response(by using the reflectance of one source detection pair as the referenceand normalizing the reflectance of other source detector separationpairs to the reference). The normalized reflectance versussource-detector separation is then fit to a diffusion model by a leastsquare minimization algorithm to determine the absorption and reducedscattering spectra. The recovered absorption spectra are fit linearlywith known chromophore absorption spectra to extract chromophoreconcentrations, and the reduced scattering spectra are fit to ascattering power law to obtain the scattering power. The probe is usedto determine the skin optical properties sclera and also extract thechromophore concentrations and the scattering power of sclera It isfound that performing the “two-region chromophore fitting” to theabsorption spectrum would result in the best fit with minimal residuals.Two-region chromophore fitting, as used herein, may mean that the scleraabsorption spectrum is fit to a set of known chromophore absorptionspectra at wavelengths between, e.g., 500 nm and 600 nm, and again fitseparately between, e.g., 600 nm and 1000 nm. The rationale forperforming the two-region fitting is that the sclera has very differentoptical properties in the visible and the NIR wavelength regions, andthus the sampling volumes at these two regions are quite different.Likewise, the best fittings for reduced scattering coefficients of skinwere obtained when the reduced scattering spectra were fit in the regionbelow and above 600 nm separately. The scattering power is not onlydependent to anatomical location but also on sclera layer. These systemsand methods are capable of studying in-vivo superficial tissue atdifferent depths simultaneously. Significantly different hemoglobinconcentration at the targeted scleral tissue and untargeted adjacentanatomy is also disclosed in various embodiments.

In some embodiments, the system can include a diffusing probe used withmultimodal fibers for both penetration and detectors. Reflectance can bemeasured through multiple layers, plurality of depths and capable ofsimultaneous depths. Diffuse reflectance spectroscopy as a tool tomeasure the absorption coefficient in sclera with integrated in-vivoimaging of tissue absorption scattering and hemoglobin concentration formeans of injury prevention depth control and anatomy avoidance guidancefor laser surgery and observation of in vivo micropore biometry andongoing wound healing changes in tissue.

In a laser treatment, the optical properties (absorption and scatteringcoefficients) are important parameters. The melanin content of a tissueinfluences the absorption of light in the skin. A diffuse reflectanceprobe consisting of a ring of six light delivery fibers and a centralcollecting fiber system is proposed to measure the diffused reflectedlight from sclera. The absorption coefficient can be calculated fromthese measurements. The system of the present disclosure may be capableof real-time in-vivo technique to determine the absorption coefficientof desired target tissue in the sclera over multiple layers of thesclera at multiple depths. Three sources of signals that affect theintensity of diffusely reflected light derive from characteristic ofconnective tissue. (1) Light scattering changes, both fast (over 10 s ofmilliseconds) and slow (i.e., >˜0.5 s), (2) early (˜0.5-2.5 s)absorption changes from alterations in chromophore redox status, i.e.,the oxy/deoxy-hemoglobin ratio (known as the “initial dip” period), and(3), slower (˜2-10 s) absorption changes due to blood volume increase(correlated with the fMRI BOLD signal). Light scattering changes havebeen attributed to interstitial volume changes resulting from cellularhydration, water content, water movement, and capillary expansion.

Quantitative diffuse optical methods such as spatially-resolvedreflectance, diffuse optical spectroscopy (DOS), and tomography (DOT),and diffuse correlation spectroscopy (DCS) possess exquisite sensitivityto functional and structural alterations in connective tissue. Someembodiments can utilize the near-infrared spectral region (600-1000 nm)to separate and quantify the multispectral absorption (μ_(a)) andreduced scattering coefficients (μ_(s)′), providing quantitativedetermination of several important biological chromophores such asdeoxy-hemoglobin (HbR), oxy-hemoglobin (HbO₂), water (H₂O), and lipids.Concentrations of these chromophores represent the direct metrics oftissue function such as blood volume fraction, tissue oxygenation, andhydration. Additionally, the scattering coefficient can containimportant structural information about the size and density ofscatterers and can be used to assess tissue composition (extracellularmatrix proteins, cell nuclei, mitochondria) as well as follow theprocess of tissue remodeling (wound healing, etc.). The system utilizesa limited number of optical wavelengths (e.g., 2-6) and a narrowtemporal bandwidth, but forms higher resolution images of subsurfacestructures by sampling a large number of source-detector “views.” Toachieve maximal spatial resolution, the ideal DOT design may employthousands of source-detector pairs and wavelengths. The system of thepresent disclosure may further employ a non-contact quantitative opticalimaging technology, modulated imaging which is capable of bothseparating and spatially-resolving optical absorption and scatteringparameters, allowing wide-field quantitative mapping of tissue opticalproperties. It may use spatially modulated illumination for imaging oftissue constituents. Periodic illumination patterns of various spatialfrequencies are projected over a large area of a sample. The diffuselyreflected image is modified from the illumination pattern due to theturbidity of the sample. Sine-wave illumination patterns are may beused. The demodulation of these spatially modulated waves characterizesthe modulation transfer function (MTF) of the material and embodies thesample optical property information. Color coding may be incorporatedinto the software to allow for color assignment and viewing of overlayon the displayed 3D converted image. Artificial intelligence recognitionof color assigned anatomical distinctions may be incorporated, therebyallowing for real time identification of tissue variance betweentargeted tissue and adjacent anatomy and incorporation of color assigned3D integrated conversion display of image sample. Anatomy avoidancetechnology primarily focused on blood vessels and sub surface tissue viause of optical properties of the tissues using reflective spectroscopy,biofeedback loop and a video camera.

Referring to FIG. 26-A, an exemplary multilayer imaging platform 2600 isillustrated, according to some embodiments of the present disclosure.The platform 2600 may include: HL—Halogen Lamp; MS—Mirror systemDD—digital Driver; L2—projection lens; L3—camera lens; LCTF—liquidcrystal tunable filter; and CCD VC—CCD Video Camera, or other suitablevideo camera. FIGS. 26-B and 26-C illustrate an exemplary CCD camerawith nozzle. FIG. 26-D illustrates an exemplary camera view using theCCD camera. Other suitable cameras may be used. In some embodiments, theplatform may include solid state laser wavelength Er:YAG 2.94 μm, freerunning system with scanning and long working distance platform,procedure performed in slit lamp sitting position, physiciancontrolled/software dependent, procedure time several minutes both eye,etc.

In some embodiments, a method for quantitatively mapping tissueabsorption and scattering properties is provided, and thereby allowinglocal sampling of in vivo concentrations of oxy- and deoxy-hemoglobincan be used for selective identification and distinguishing of targettissues and untargeted tissues for purposes of surgical planning andlaser guidance for laser surgery of the sclera. Consistent dynamicchanges in both scattering and absorption highlight the importance ofoptical property separation for quantitative assessment of tissuehemodynamics. The systems and methods of the present disclosure mayintegrate general platforms of spatially modulated structuredillumination using speckle correlation and fluorescence. The systems andmethods may then be used in an in vivo real-time intraoperative settingto provide feedback and guidance for surgeons. 3D conversion of thereconstructed image can be viewed simultaneously by CCD video camera incolor code assignments to exploit anatomy avoidance software andtargeted treatments which can be modified intraoperatively. The systemmay be used further postoperatively in order to view microporated tissuesubsurface biometry, physiology, wound healing and morphology forfurther guidance and treatment implications.

Use of Fluorescence: The sclera has only 25% of the total GAG's that arepresent in the cornea. Because the GAG's attract water, the sclera isless hydrated than the cornea (but not 75% less; due to severalstructures that carefully maintain a lower hydration level in thecornea). The large variation in fibril size and the irregular spacingbetween scleral components leads to light scattering and opacity. Thecolor of the sclera is white when healthy, but can discolor over time ordue to illness (e.g., hepatitis). Internally, the sclera merges with thechoroidal tissue in the suprachoroid layer. The innermost scleral layeris called the lamina fusca, as described herein. All of these have aspecific fluorescence, spectral property and water content.

Fluorescence and diffuse reflectance spectroscopy are powerful tools todifferentiate one connective tissue to the other based on the emissionsfrom endogenous fluorophores and diffuse reflection of absorbers such ashemoglobin, melanin, water, protein content etc. However, separateanalytical methods are used for the identification of fluorophores andhemoglobin. The estimation of fluorophores and hemoglobin simultaneouslyusing a single technique of auto fluorescence spectroscopy can beperformed. The diagnostic and real time treatment selection of targetedand untargeted in vivo tissues are important technical features herein.Emissions from prominent fluorophores collagen, flavin adeninedinucleotide, phospholipids, and GAGS, Proteoglycans are analyzed apriori and can also be assigned color tags. The water concentration canalso be calculated from the ratio of fluorescence emissions at 500 and570 nm. A better classification of normal and tumor tissues is yieldedfor 410 nm excitation compared to 320 nm when diagnostic algorithm basedon linear discriminant analysis is used. Fluorescence spectroscopy as asingle entity can be used to evaluate the prominent fluorophores as wellas the water concentration within gradient tissues and segregated tissuestructure and components.

Fluorescence spectroscopy is a tool used to differentiate targeted anduntargeted tissues based on the emission spectral profile fromendogenous fluorophores. Fluorescence estimates the concentration offluorophores using auto fluorescence spectroscopy and to utilize itsdiagnostic inputs on in vivo tissues of clinical importance and toutilize that information as laser guidance software code platform via areal time biofeedback loop. Fluorescence emissions of the scleraltissues are recorded at excitation wavelengths of 320 and 410 nm. Theemission characteristics of fluorophores such as collagen, nicotinamideadenine dinucleotide (NADH), flavin adenine dinucleotide (FAD),phospholipids and porphyrins, proteoglycans, GAGs, Collagenextracellular matrix and melanocytes of scleral tissues and adjacentanatomical tissues such as blood vessels, veins, nerves etc. areelicited. Exact tissue classification is then carried out using thespectral intensity ratio (SIR) and multivariate principal componentanalysis-linear discriminant analysis (PCA-LDA). The diagnosticalgorithm based on PCA-LDA can provide better classification efficiencythan SIR. Moreover, the spectral data based on an excitation wavelengthof 100 nm to 700 nm in particular may be more efficient in theclassification than 320 nm excitation, using PCA-LDA. Better efficacy ofPCA-LDA in tissue classification can be further confirmed by thereceiver operator characteristic (ROC) curve method. The results of thisinitial data capture represent a system and method of the presentdisclosure for using fluorescence spectroscopy based real time tools forthe discrimination of various connective tissue components in thisembodiment of the scleral connective tissue of the eye from the adjacentuntargeted tissue, which may present a huge challenge. This anatomyavoidance system can be reiterated using real time imaging, e.g., OCTimaging sensors as well as chromophore sensors (water, color etc.) orspectroscopy without fluorescence.

There are many biological molecules which can absorb light viaelectronic transitions. Such transitions are relatively energetic andhence are associated with absorption of ultraviolet, visible andnear-infrared wavelengths. The molecules generally have a string ofdouble bonds whose pi-orbital electrons act similar to the electrons ina metal in that they collectively behave as a small antenna which can“receive” the electromagnetic wave of a passing photon. If the resonanceof the pi-orbital structure matches the photon's wavelength then photonabsorption is possible. The systems of the disclosure described hereinmay utilize these electrical vibrations to give biofeedback to the lasermodule thereby distinguishing not only targeted and untargeted tissuesbut actual transitions in tissue from one chromophore to the nextcreating an ultrasensitive ultra-feedback loop. In addition, in thefield of infrared spectroscopy studies the variety of bonds which canresonantly vibrate or twist in response to infrared wavelengths andthereby absorb such photons. Perhaps the most dominant chromophore inbiology which absorbs via vibrational transitions is water. In theinfrared, the absorption of water is the strongest contributor to tissueabsorption and is described in this invention. All other tissues whichhave color chromophores such as blood vessels, veins, or melanin arealso described as providing biofeedback in their own specificabsorptions or vibrational transitions and further defined as tissuecharacteristics which are sensed by these laser modules and othersystems and combinations described herein.

In some embodiments color and chromophore sensing can be used to trackblood vessels and other subsurface features in the sclera and otherocular locations. Similarly, hydration sensing can also be used. Thesystems of the present disclosure may include a biofeedback sensor, ascanner including a galvanometer and a camera that provide biofeedbackthat is used to distinguish targeted and untargeted tissues in additionto the transitions within tissues from one chromophore to the next, inthe form of a sensitive biofeedback loop. Such transitions arerelatively energetic and hence are associated with absorption ofultraviolet, visible and near-infrared wavelengths. On the other hand,currently known systems in the art use simple image facilitated feedbackfor the laser module it discloses. Since many biological molecules canabsorb light via electronic transitions, sensing and monitoring them canbe useful generic imaging capabilities.

It should be noted that chromophore sensing and monitoring, which is theuse of color differences based on inherent light absorption by differentmaterials as a way to sense and monitor and determine boundaries withina tissue, is an advantageous improvement. Color sensing and monitoringprovides an advantage in that it can identify subtle differences intissue composition that can then be used for positional based avoidanceand a higher degree of accuracy in targeting only those tissue locationsdesired.

In some embodiments, features of the laser system of the presentdisclosure can include: Flash Lamp or Solid State laser wavelengthEr:YAG 2.94 μm, or other wavelengths with high water absorption nearpeaks, as shown in FIG. 26-2; Fiber optic delivery system, with fibercore between 50 μm and 600 μm, with a hand held probe & eye contacting;flash lamp pumped; physician dependent; no eye tracking; procedure time˜10 minutes per eye; physician/manual depth control.

An exemplary system functional diagram for a laser system of thedisclosure is illustrated in FIG. 3B above.

In some embodiments the features can include: solid state laserwavelength Er:YAG 2.94 μm; free space, short focal length, opticdelivery system with a hand held laser head, eye contacting; solid statelaser wavelength Er:YAG 2.94 μm diode, or other wavelengths with highwater absorption near peaks, as shown in FIG. 26-2; diode pumped; manualpositioning; 2D scanning micro pore placement; spot 50 μm to 425 μm,scleral nozzle guard; with physician/manual depth control; performedsemi-reclined; software controlled/foot pedal; monitor visualization.Exemplary system diagrams are illustrated in FIG. 3A and FIGS. 27A to27C.

Engineering advantages of the system may include: light weightcomponents, more “space” in the hand piece. Engineering advantages mayalso include: solid state laser source based in the base station,miniaturization of all components, power/energy sufficient, and others.Clinical advantages can include: easy to use, simple, less technologic,and others. Clinical challenges advantages may also include: patient eyemovements tracking, depth control, means to hold eye lid open (see,e.g., speculum illustrated in FIGS. 28A to 28C and FIGS. 29A to 29B).

In some embodiments the features may include: solid state laserwavelength Er:YAG 2.94 μm; free space, short focal length, opticdelivery system with manual control, eye contacting; solid state laserwavelength Er:YAG 2.94 μm diode, or other wavelengths with high waterabsorption near peaks, as shown in FIG. 26-2; diode pumped; manualpositioning; 2D scanning micro pore placement; spot 50 μm to 425 μm,scleral nozzle guard and foot pedal; with physician/manual depthcontrol; performed semi-reclined; software controlled/foot pedal; withvisualization camera, an articulating arm with hand piece holder andcamera and monitor visualization (as illustrated in FIG. 26A and FIG.2).

Other engineering advantages may also include: light weight components,miniaturization of all components, power/energy sufficient, stability ofthe articulating arm, camera image zoom and resolution, and others.Clinical advantages can include: easy to use, simple, less technologic,and others.

In some embodiments the features, may include: free space, long focallength optic delivery system with automatic controls, non-patientcontacting; solid state laser wavelength Er:YAG 2.94 μm, or otherwavelengths with high water absorption near peaks, as shown in FIG.26-2; diode Pumped; robotic positioning for 6 axis; 2D scanning micropore placement; 15 to 20 cm working distance with active depth control;laser power monitor sensor and controls; performed semi-reclined; handsfree/software controlled/foot pedal; eye tracking; spot 50 μm to 425 μm;eye fixation light source or LED array, ablation debris removal systemand camera/monitor visualization; procedure time˜few minutes both eyes(as illustrated in FIG. 26.1).

Further engineering advantages may include: Automation of 6 axis laserpositioning, depth control, eye tracking, eye fixation point, multipletreatment patterns, ablation material removal, reduced treatment times,surgeon hands free operation and others. Clinical advantages mayinclude: easy to use, simple, faster, no patient eye contact, improvedpore repeatability, automation, high accuracy beam deflection scanner,patient eye tracking, and depth control.

In some embodiments, the features of the free space optical deliverysystem can be combined with the features of the fiber delivery system asan additional subsystem.

Engineering advantages may include: Integration of various subsystems,controls, displays and others. Clinical advantages may include: improvedcamera and visualization, OCT and depth verification, expanded treatmentcapability using advantages of multiple beam delivery systems, andexpanded controls and functionality in controls and software.

In some embodiments, the 2.94 μm Er:YAG laser may be substituted withother wavelengths that have high water absorption as shown on awavelength vs water absorbtion plot (see FIG. 26-2) e.g., 2.0 μm andothers.

In some embodiments, the 2.94 μm Er:YAG laser may be substituted withother types of diode pump solid state (DPSS) lasers with single modeemissions and higher beam quality that could product round, square orrectangular spots.

In some embodiments, the 2.94 μm Er:YAG laser may be substituted withother types of diode pump solid state (DPSS) lasers that combinemultiple sources to achieve equivalent fluence.

In some embodiments, the 2.94 μm Er:YAG solid state laser may besubstituted with other type of lasers with equivalent fluencespecification that use shorter pulse lengths. In some embodiments thefeatures can include: a camera that may provide both high resolution,color images; a zoom range to see entire eye or the bottom of the porefor the surgeon and allow them to monitor the treatment protocol andhave the opportunity to terminate and shut off the laser if needed; anelectronic signal interface to allow the system to gain image data. Thecamera may also provide system controls when used with internal imageprocessing and analysis to provide eye position and automatic centeringof the patient eye for treatment, input for eye tracking software,background image to super impose treatment areas on the image of thepatient's eye. The Camera can be positioned off the laser axis (see FIG.20F) to enable field of view to see the treatment area, the entire eyeand to see features of the patient eye to lock eye tracking to.

Engineering advantages may include: Integration of a camera images andanalysis with the eye tracking and laser beam delivery systems andcontrols software. These features may mitigate potential risks; keep thedoctor/user in control of the treatment. Clinical advantages mayinclude: Improved surgeon visualization and overall control of thetreatment, risk mitigation of eye movement, and others.

In some embodiments the features can include: Depth control monitored byOCT and/or other technologies and may control the remaining scalarthickness below the bottom of the pore without interrupting thetreatment while ensuring that depth of the pore limits are not exceeded.The OCT and/or other sensor may be merged into the laser beam axis andoptical may match the focal length to the laser beam delivery system sothe OCT and/or other system will work as a focal sensor for the OCTand/or system and laser system. The OCT and/or other system may samplepore depth continually, the sample rate will provide verificationbetween laser pulses or during laser pulses enabling the laser emissionsto be immediately terminated (refer back to FIG. 4B-1 for an exemplaryOCT system).

Engineering advantages may include: Integration of an OCT system withthe laser beam delivery system and controls software. Clinicaladvantages may include: Reduce surgeon dependences, risk mitigation forsclera perforation, improved pore depth and repeatability, and others.

In some embodiments, a long working distance system may be preferredbecause 1) it gives more engineering flexibility to fully feature theprocedure, including improved: eye tracking, depth control, positioningaccuracy, lighting and visualization, plume evacuation, and costadvantages; 2) less invasive, no contact—ultra minimally invasive; 3)automated control, reliable, predictable outcomes; 4) user and patientsafety; 5) “No Touch” procedure; and others.

In some embodiments the features can include: Robotics to position thelaser beam delivery system centerline, e.g., in 6 axis position, toposition the centerline of the laser on the center of the eye globe, ata distance to focus the beam spot on the surface of the sclera; a meansto rotate the laser beam delivery system around the eye for 360° ofrotation to perform all treatment patterns comprised of individualablated pores (See examples shown in FIGS. 20E, 20G, and 20H).

In some embodiments the features of the robotics to position the laserbeam delivery system can include: long focal length optical, 10-20 cm, agalvanometer scanners to position x and y, an angular motion controls toscan in y only and then step x, an auto-focus controls to correct z,focus to an individual patient, means to ablate quadrants in subquadrant sections with combination of x and y moves and reduced motionof the x,y scanner beam motion. The robot could control multiple axes,e.g., 6 axes similar to a coordinate measuring machine; the laser beamdelivery system could be mounted to a rotary mechanism on symmetricalaxis of the patient's eye controlling various axis with an x,y scannerand focus mechanism and others (See example shown in FIG. 20I).

Other features may include stability, speed, small angular precision inthe x,y scanner(s), mass of the moving system. The Clinical advantagesare hands off operation, limited surgeon training and manual skills,reduced treatment time, non-contact with patient and others.

In some embodiments, patient may still move eyes to required position. Afixation target may shift to each of the 4 quadrants, or sub-treatmentareas (see, e.g., FIG. 2B-2) in a quadrant and robotic or joy stickposition may have to track eye position, including: superior nasal;superior temporal; inferior nasal; inferior temporal. Visualization ofeach quadrant and laser ablation/image with hand held system may beprovided. Eye fixation position may be integral to the positioning ofthe treatment area on the eye based on the specifics of the patient. Theability to shift the eye fixation point can provide a means for vascularavoidance in shifting the treatment area. Movements in the fixationpoint provide a means to move the center of the treatment position onthe eye. Also included is a means to break up a large treatment patterninto smaller ablation areas, a mosaic of the full treatment area,reducing the incident angle of the beam to the surface of the eye at anypoint and negating the need to move the laser beam delivery system.

In some embodiments, the fixation point may be comprised of a single ormultiple illumination sources; selectively illuminated based on locationrelative to the laser beam. The illumination sources could move with thelaser delivery system or have multiple sources in predefined locations.The illumination source could be an LED or array of LED's, individuallyaddressable. The fixation point location can be fixed or controlled aspart of the eye tracking system in combination with laser beampositioning.

In some exemplary operations, zone treatment simulations may beperformed, including: baseline model with sclera stiffness andattachment tightness altered in individual full zones: treatedcombinations of zones (with and without changing attachment): forexample, individually: 0, 1, 2, 3, 4; combined: 1+2+3, 1+2+3+4,0+1+2+3+4; effective stiffness: modulus of elasticity (E)=1.61 MPa,equivalent to −30 years old; loose attachment between the sclera and theciliary/choroid where values in original accommodation model are used.£See, e.g., FIG. 35).

Effect of zone treatment on ciliary deformation in accommodation mayinclude sclera stiffness, sclera stiffness+attachment.

In some embodiments, different treatment region shapes may be applied toone sclera quadrant with reference to multiple (e.g., 3 or 5) criticalzones baseline simulation: original model of healthy accommodation with“old” sclera: stiff starting sclera: modulus of elasticity (E)=2.85 MPa,equivalent to ˜50 years old; tight attachment between the sclera and theciliary/choroid, all other parameters changed (ciliary activation,stiffness of other components, etc.).

In some exemplary operations, shape treatment simulations may include:baseline model with regionally “treated” sclera stiffness: treateddifferent area shapes (without changing attachment)→treated stiffness:modulus of elasticity (E)=1.61 MPa, equivalent to ˜30 years old;effective stiffness in each zone may be determined by amount of shapearea in each zone and values in original accommodation model.

Effect of shape treatment on ciliary deformation in accommodation mayinclude sclera stiffness only.

Treated stiffness may depend on: pore volume fraction in the treatedregion→% sclera volume removed by treatment; pore volume fraction isvaried by changing parameters of ablation holes; and others. Resultantstiffness estimated as microscale mixture: holes assumed to be parallelevenly spaced/sized within volume=volume fraction (% of total scleravolume); remaining volume is “old” sclera (E=2.85 MPa); need to remove˜43.5% of volume to change sclera stiffness in the treated area from old(e.g., 50 year-old) to young (e.g., 30 year-old); protocols(combinations of density % & depth) allow for a maximum volume fractionof 13.7%, equivalent to a new stiffness of 2.46 MPa; array size=sidelength of the square area of treatment (mm).

The following parameters are considered. (See also FIGS. 26-3A, 26-3A1,26-3A2, and 36).

Exemplary model outcomes are shown in FIG. 41.

Treated surface area=surface area of sclera where treatment is applied(mm{circumflex over ( )}2), where treated surface area=array squared.

Thickness=thickness of sclera in the treated area (mm), assumed uniform.

Treated volume=volume of sclera where treatment is applied(mm{circumflex over ( )}2) treated volume=treated surfacearea*thickness=array²*thickness.

Density %=percent of treated surface area occupied by pores (%).

Spot size=surface area of one pore (mm{circumflex over ( )}2).

# pores=number of pores in the treated region.

$\begin{matrix}{{\#{pores}} = {\frac{{density}\mspace{14mu}\%*{treated}\mspace{14mu}{surface}\mspace{14mu}{area}}{{spot}\mspace{14mu}{size}*100} = {\frac{{density}\mspace{14mu}\%*{array}^{2}}{{spot}\mspace{14mu}{size}*100}*{round}\mspace{14mu}{to}\mspace{14mu}{nearest}\mspace{14mu}{whole}\mspace{14mu}{{number}.}}}} & \;\end{matrix}$

Total pore surface area=total area within the treated surface areaoccupied by pores

${{total}\mspace{14mu}{pore}\mspace{14mu}{surface}\mspace{14mu}{area}} = {{{spot}\mspace{14mu}{size}*{pores}} \approx \frac{{density}\mspace{14mu}\%*{treated}\mspace{14mu}{surface}\mspace{14mu}{area}}{100} \approx \frac{{density}\mspace{14mu}\%*{arra}y^{2}}{100}}$

Depth=depth of one pore (mm); dependent on pulse per pore (ppp)parameter

depth %=percent of the thickness extended into by the pore.

${{depth}\mspace{14mu}\%} = {\frac{depth}{thickness}*100}$

As shown in FIG. 26-3A, total pore volume=total area within the treatedsurface area occupied by pores.

Volume fraction=percent of treated volume occupied by pores (%), i.e.percent of sclera volume removed by the laser.

${{volume}\mspace{14mu}{fraction}} = {{{\frac{{total}\mspace{14mu}{pore}\mspace{14mu}{volume}}{{treated}\mspace{14mu}{volume}}*100} \approx \frac{{density}\mspace{14mu}\%*{depth}}{thickness}} = \frac{{density}\mspace{14mu}\%*{depth}\mspace{14mu}\%}{100}}$

Relationships between treatment parameters include: input parameters oflaser treatment; properties of the sclera; input to calculate newstiffness.

Calculating new stiffness of sclera in the treated region.

Volume fraction=percent of treated volume occupied by pores (%), i.e.percent of sclera volume removed by the laser.

${{volume}\mspace{14mu}{fraction}} = {{{\frac{{total}\mspace{14mu}{pore}\mspace{14mu}{volume}}{{treated}\mspace{14mu}{volume}}*100} \approx \frac{{density}\mspace{14mu}\%*{depth}}{thickness}} = \frac{{density}\mspace{14mu}\%*{depth}\mspace{14mu}\%}{100}}$

Stiffness=modulus of elasticity of sclera before treatment (MPa).

Treated stiffness=modulus of elasticity of sclera after treatment (MPa);estimated from microscale mixture model.

$\begin{matrix}{{{treated}\mspace{14mu}{stiffness}} = {{{\left( {1 - \frac{{volume}\mspace{14mu}{fraction}}{100}} \right)*{stiffness}} \approx {\left( {1 - \frac{{density}\mspace{14mu}\%*{depth}}{{thickness}*100}} \right)*{stiffness}}} = {\left( {1 - \frac{{density}\mspace{14mu}\%*{depth}\mspace{14mu}\%}{10000}} \right)*{stiffness}}}} & \;\end{matrix}$

Input parameters of laser treatment: properties of the sclera, input tocalculate new stiffness input to finite element model of treated zones,effect of volume fraction on ciliary deformation in accommodation:sclera stiffness only, full zone region treated (region fraction=1).

Protocols=range of possible combinations of density % and depth, sclerain all zones changed to treated stiffness corresponding with pore volumefraction.

Effect of volume fraction on ciliary deformation in accommodation:sclera stiffness+attachment, full zone region treated (regionfraction=1), healthy=original accommodation model results.

Protocols=range of possible combinations of density % and depth, sclerain all zones changed to treated stiffness corresponding with pore volumefraction effect of volume fraction on ciliary deformation inaccommodation: sclera stiffness+treatment area shape.

Protocols=range of possible combinations of density % and depth, sclerain all zones changed to treated stiffness corresponding with pore volumefraction and region fraction of treated area.

J/cm2 calculation: J/cm2×Hz (1/sec)×Pore size (cm2)=W; J/cm2=W/Hz/poresize. Example: spot is actually a “square”, therefore the area would bebased on square calculation: 7.2 J/cm2=1.1 w/300 Hz/(225 μm 10⁻⁴)².

Factors that may affect ablation depth % on living eyes in surgeryinclude: moisture content on surface and inside the tissue, tenon orconjuntiva layer, laser firing angle, thermal damage, may consider waterspray, Cryo spray/refrigerated eye drops, Cryo hydrogel cartridge in thelaser disposable system (perioperative medications such asantibiotics/steroids).

In some embodiments, the described systems, methods and devices of thedisclosure may include following features.

Adjustable micropore density: dose and inflammation control could beachieved thanks to a variable number of micropores created perapplication area. Adjustable micropore size; dose and flexiblepatterning of microporation. Adjustable micropore thermal profile: thesystem can create micropores with adjustable thermal profiles thatminimize creation of a coagulation zone. Adjustable depth with depthrecognition: the system creates micropores in a controlled manner andprevent too deep ablation Anatomy recognition to avoid blood vessels.(FIG. 26-4 illustrates exemplary anatomy recognition.) Laser securitylevel: the device is a Laser Class 1c device, the system detects the eyecontact and the eye pod covers the cornea. Integrated smoke evacuationand filtration: fractional ablation can be conducted without any extraneed in installing a smoke evacuation system, since smoke, vapor andtissue particles will be sucked out directly by integrated systems.Laser system will have an integrated real time video camera (e.g., anendo camera, CCD camera) with biofeedback loop to laser guidance systemintegrated with GUI display for depth control/limit control. (See FIG.26-4-1).

In some embodiments, the described systems, methods and devices of thedisclosure may provide: Laser system biofeedback loop integrateschromophore recognition of color change using melanin content (computerintegration of various micropore staging for color change; a prior depthinformation in the 3 zones of thickness; laser system capable ofintegrating a priori scleral thickness mapping for communication withlaser guidance planning and scleral microporation; use of OCT or UBM or3D tomography; laser system programming release code with controlledpulses per procedure; electronically linked to reporting to a datareport (calibration data, and service data, statistics etc.). Lasersystem components may be built in modular fashion for easy servicemaintenance and repair management. Self-calibrating setup as well asreal time procedure calibration prior to treatment, after treatment andbefore subsequent treatment may be included. All calibrations may berecorded in database. Other features may include communication port foronline communication (e.g., WIFI service trouble shooting, reportgeneration, and communication to server, WIFI access to diagnosticinformation (error code/parts requirement), and dispense either troubleshooting repair and maintenance or dispense an order for service byservice representative). Some embodiments may include spare partsservice kit for service maintenance and repair for onsite repair; lasersystem key card integration with controlled pulses programming with timelimitation included; aiming beam with flexible shape to set boundaryconditions and also to trigger if the laser nozzle is on axis, level andpositioning; aiming beam coincident with alignment fixation beam totrigger system Go No Go for starting treatment ablation; laser systemrequirements containing an eye tracking system and corresponding eyefixation system for safety of ablation to control for eye movement;laser system requirements having ability to go ‘on axis’ deliverythrough a gonio mirror system to deliver microporation on the sclera, orthrough a slit lamp application or free space application. These mayrequire higher power, good beam quality as well as integration offixation target and/or eye tracking system. Good beam quality may mean:laser system focusing down to 50 μm and up to 425 μm. The laser systemmay be capable of doing a quick 360dg procedure through galvos scanningand use of robotics to change quadrant treatments within 40-45 secondsper whole eye (e.g., 4 quadrants in each eye about 10 seconds perquadrant; 1-2 seconds repositioning laser to subsequent quadrant). Thelaser system may be a workstation with integration of foot pedal,computer monitor; OCT; CCD video camera and/or microscope system. Thelaser system may include patient positioning table/chair module that isflexible from supine position; flexible angle; or seated; and motorizedchair.

In some exemplary operations, the described systems, methods and devicesof the disclosure may include the following medical procedure: 1) Theuser manual may give information about the correct handling of thesystem. 2) Put the eye-applicator onto the treatment area and place theapplicator unit on the eye-applicator. 3) The user can set the treatmentparameters. 4) The user starts the treatment procedure. 5) The user maybe informed about the on-going state of the treatment. 6) The user maybe informed about the calibration of the energy on the eye before andafter the treatment. 7) To prevent undesired odors, ablation smoke maybe prevented from spreading. 8) The user may be informed about thevisualization of the eye during the treatment, between quadrants andafter the treatment.

In general, the system will have low maintenance. A system service, ifnecessary, may be conducted as fast as possible, leading to a minimaldowntime. Furthermore, service costs may be lower than with common lasersystems. The applicator unit, eye-applicator and the disposable insertmay be easy and hygienic to handle, especially while attaching anddetaching. Software may allow data exchange between the device and acomputing device.

Microporations—Exemplary Parameters

Term Definition Procedure full eye - 4 quadrants Treatment siteProcedure: average area 300 cm2 (=mean value) and size partialtreatments: average area 50 cm2 Scenarios Maximal utilisation caseExpected utilisation case No. of treatments per day Array size 5 mm(Variable between 5 mm (Variable between 2 mm-14 mm) 2 mm-14 mm)“Standard” microporation (MP) parameters; based on preliminaryexperiments: MP1 300 Hz repetition rate, 125 μs laser pulse duration, 5pulses per pore, 5% MP2 200 Hz repetition rate, 175 μs laser pulseduration, 5 pulses per pore, 7% MP3 100 Hz repetition rate, 225 μs laserpulse duration, 7 pulses per pore, 8% MP4 200 Hz repetition rate, 225 μslaser pulse duration, 5 pulses per pore, 6%

Service requirements may include: Maximum every year or after apredetermined number of procedures, e.g., 1000, 2000, or 3000procedures, whatever occurs first. Overall product life time: allcomponents may be evaluated to withstand a product life time of, e.g.,at least 5 years.

System operation may be through pre-approved electronic key card.Visualization required during surgery: Lighting of eye to aidvisualization to be provided—either external light source orincorporated into laser adaptor fixation device, a video camera and GUIinterface to computer monitor may be a required module. Patient can bein horizontal or inclined or seated position. Shielding for eye safetyof patient during procedures may be needed. Operation: The system mayallow activating the laser when applicator and insert are attached, onproper tissue contact and with verified user access. Pore depth monitor:maximum depth monitored by end switch (optical or equal monitored).Management of eye movement intra-procedure: Eye tracking technology withcorresponding eye fixation targets may be included for fully non-contacteye procedure. Vasculature avoidance: Scan/define ocular vasculature maybe provided to avoid microporation in this area. See FIGS. 4A-1 to 4A-10which illustrate how microporation/nanoporation may be used to removesurface, subsurface and interstitial tissue and affect the surface,interstitial, biomechanical characteristics (e.g., planarity, surfaceporosity, tissue geometry, tissue viscoelasticity and otherbiomechanical and biorheological characteristics) of the ablated targetsurface or target tissue.

Performance requirements may include: Variable pore size, pore arraysize and pore location. Exemplary preparation time: 5 min from power-onof the device until start of microporation process (assuming averageuser reaction time). Robotics incorporation by quadrant to achievetreatment time requirements. Treatment time may be <60 s, 45 s for oneprocedure. Diameter of micropores: Adjustable between 50 μm-600 μm.Tissue ablation rate: adjustable between 1 to 15%. Microporation arraysize: Area adjustable up to between 1 mm×1 mm and up to 14×14 mm, squareshaped pore custom shape array. Multiple ablation pattern capability.Short press to activate and deactivate laser: the actual microporationprocess may be started by pressing a foot switch only for a short amountof time, instead of pressing it during the entire microporation.Stopping the laser can be done identically. Ablated hole depth: 5% to95% of scleral thickness. Biocompatibility: All tissue contact parts areto be constructed with materials that are in compliance with medicaldevice requirements.

In some embodiments, the system may include: laser wavelength: 2900nm+/−200 nm; around the mid IR absorption maximum of water. Maximumlaser fluency: ≥15.0 J/cm² on the tissue ≥25.0 J/cm² on the tissue; towiden treatment possibilities 2900 nm+/−200 nm; around the mid IRabsorption maximum of water. Laser setting combinations: Laserrepetition rate and pulse duration may be adjustable by usingpre-defined combinations in the range of 100-500 Hz and 50-225 μs. Saidrange may be a minimum range, e.g., ≥15.0 J/cm² on the tissue, or ≥25.0J/cm² on the tissue, to widen treatment possibilities. Aggressivetreatments number of pulses per pore: “Aggressive” settings may also beselectable to create micropores far into the dermis, e.g. with adepth >1 mm. As the depth is mainly fluence-controlled, a high number ofpulses per pores should automatically lead to larger depth values.Therefore, the pulse per pore (PPP) values may be adjustable between:1-15PPP. Shock and vibration: Device may withstand a lorry transportwithin the supplied single-use or multiple-use (in case of service orrepair) packaging. Prevention of odour spreading: A system to reduce thespreading of unpleasant odour to a minimum may be implemented. GUI: Theuser interface may be supported by a reasonable display size. Audiblenoise: The maximum noise generated by the system (cooling and evacuationsystem at 100%) may not exceed 70 dBA or 50 dBA. Shock absorbance of theunit: The unit may tolerate a fall of certain height without any majordamage which causes the system to fail. System connectivity with one ormore of USB, LAN, WLAN, Bluetooth, Zigbee, or other suitabletechnologies.

In certain embodiments, the physical requirements of the systemdescribed herein may include these exemplary parameters: Laser Systemmay be incorporated into a “Cart” type workstation unit with lockablewheels and counter balanced/articulated arm as to prevent tipping of thecart during use or transport (See FIGS. 24 and 26-5). No Tiltrequirement. Weight: Weight (Cart+counter balance/articulated arm): <100kg. Ancillary equipment: video monitoring system, e.g. used inconjunction with standard oculars, etc. Temperature and Relativehumidity specifications for shipment and use: Humidity: <70% RH,non-condensing; Operating temperature: 18 to 35° C.; Humidity: <70% RH,non-condensing; Storage and transport temperature: −10 to 60° C.

Design and Usability: The usability of the design may fulfill thegeneral needs of the targeted user groups, including lead users,doctors, and medical staff. Weight balance: The weight balance of theunit may achieve market acceptance. Shape of applicator unit: The shapeof the unit may be optimized. Radius of action: The connection betweenthe table-top unit and the handheld unit may allow an action radius ofat least 1.2 m. Good view to see proper positioning of the eye: The usermay be able to verify the proper positioning of the laser on the eyetissue. Convenient handling of applicator and insert: Applicator andinsert may be easily attachable and detachable.

Permitted application areas on human body: Generally, the device may beapplied to the eyes. Biocompatibility: All tissue contact parts are tobe constructed with materials that are in compliance with medical devicerequirements.

Accessories may include: Applicator insert (disposable part): Adisposable part to collect ablated tissue which establishes a hygienicinterface between device and tissue. Eye pod (optional): The applicatormay be reusable, easy to clean, bio-compatible, and sterilisable. FootSwitch: Foot switch operation for standard laser delivery.

In some embodiments, the systems described in the present disclosure mayinclude construction of a system that uses a pulsed, 2.94 μm Er:YAGlaser, along with a handheld probe, to ablate holes in the sclera, tomodify the plasticity of a region of the sclera, in the treatment ofpresbyopia and other eye dysfunctions.

In some embodiments, the system may include parts of a PLEASE™ Platformand additionally a 3Mikron™ Class IV Er:YAG fractional laser system. Themain parts may be: a laser module (e.g., module 2610 illustrated in FIG.26-1), a spherical shaped application (e.g. Saucer) module including:3Mikron™ DPM-2 (Er:YAG), Scanning unit & eye tracking, a robotic stagefor positioning, touchscreen control display, camera system, microscope,suction system, depth detection system, lighting and laminar air flow,aiming beam. A mobile cart module can include: power supply, touchscreencontrol display for non-surgical personal, control and cooling unit,DriCon™ Platform, wireless foot pedal, and others.

In some embodiments, some or all of the system can be easily positionedover the patients face. The laser module (see, e.g., module 2610illustrated in FIG. 26-1) may allow establishing a local sterileenvironment utilizing laminar airflow inside. The laser module may covermost or all relevant parts of the treatment procedure, such as themechatronic motion system, that moves the laser with high precision tothe selected treatment area on the sclera.

The system may include ability to assure control of ablation depth andwarning/control feature that can reliably detect the depth of the tissueablation and ultimately the interface between the sclera and choroid andeffectively prevent ablation beyond the sclera, ability of the system tobe ergonomically and clinically practical as well as acceptable for useby the physician, high reliability and controls to assure patient safetyand re-producibility of the procedure, ability to scan with a largerworking distance in order to produce a fast procedure.

In some embodiments, the system includes a display which included in thelaser module (such as module 2610 in FIG. 26-1) to view the tissue area(doctors display), control & safety (see also below) which includeslaser supply, electronics and motion control platform as well as safety,direct interface to a base station (e.g., base station 2620 illustratedin FIG. 26-1). The system may also include motion stage: Translationstage to position the laser & optics & scanner in the specific area,laser and optics: 3mikron module and beam forming optics, depth controlsystem to avoid too deep ablation, eye tracking module, suction andlaminar flow for operator safety. Beam deflection synchronized with eyetracking for micropore array generation. Other components and featuresinclude: camera unit for vision. The base station may be an intelligentmoveable base station that may include operator display for control andsafety, distribution of power to different modules, water cooling oflaser system, optional foot pedal, communication interface with externalworld, debug, updates, and other features, and main supply for widerange power supply for international operation.

As mentioned above, in some embodiments, the described systems, methodsand devices of the disclosure may include creating a finite elementmodel of the accommodative mechanism that includes seven major zonulepathways and three ciliary muscle sections, calibrating and validatingthe model through comparison to previously published experimentalmeasurements of ciliary muscle and lens motion during accommodation, andusing the model to investigate the influence of zonular anatomy andciliary muscle architecture on healthy accommodative function. The modelmay include geometry of the lens and extra-lenticular structures andsimulations utilized novel zonular tensioning and muscle contractiondriven accommodation.

In some embodiments, the described systems, methods and devices of thedisclosure may include a method to change the biomechanical propertiesof biological tissue using a complex of matrix formations consisting ofperforations on said tissue where the configuration is based on amathematical algorithm. The change in biomechanical properties ofbiological tissue is related to elasticity, shock absorption,resilience, mechanical dampening, pliability, stiffness, rigidity,configuration, alignment, deformation, mobility and/or volume of saidtissue. The matrix formations of perforations may allow for anon-monotonic force deformation relationship on said tissue with therange of isotropic elastic constant across the medium. Each matrixformation may create a linear algebraic relationship between row lengthand column length with each perforation of said tissue having continuouslinear vector spaces with derivatives up to N. Where N is an infinitenumber. The complex may create a total surface area wherein eachperforation has a proportional relationship to the total surface area ofsaid tissue. The complex can also be arranged to achieve equilibrium offorces, stress and strain and reduce shearing effect the between thematrix formations and the perforation. Each perforation may be excisedvolume of tissue which defines a point lattice on said tissue where thepreferred shape of excised volume is cylindrical. The matrix formationconsists of tessellations with or without a repeating pattern whereinthe tessellations are Euclidian, Non-Euclidean, regular, semi-regular,hyperbolic, parabolic, spherical, or elliptical and any variationtherein. Each perforation may have a linear relationship with the otherperforations within each matrix formation and the complex of matricesindividually. The tessellations directly or indirectly relate to stressand shear strain atomic relationships between tissues by computing themathematical array of position vectors between perforations. The atomicrelationship is a predictable relationship of the volume removed by eachperforation to the change in biomechanical properties seen as an elementof the mathematical algorithm. The predictable relationship of theremoved volume may be mutually exclusive. The tessellations may be asquare which can be subdivided into a tessellation of equiangularpolygons to derivative of n. In some embodiments, the mathematicalalgorithm uses a factor Φ or Phi to find the most efficient placement ofmatrices to alter the biomechanical properties of said tissue. Thefactor Φ or Phi may be 1.618 (4 significant digits) representing anyfraction of a set of spanning vectors in a lattice having the shortestlength relative to all other vectors' length. In some embodiments, themathematical algorithm of claim 1 includes a nonlinear hyperbolicrelationship between planes of biological tissue and at any boundary orpartition of neighboring tissues, planes and spaces in and outside ofthe matrix.

In some embodiments, the described systems, methods and devices of thedisclosure may include a protection lens 2700 as illustrated in FIGS.27A to 27C.

In some embodiments, the described systems, methods and devices of thedisclosure may include speculum 2810/2820/2830 as illustrated in variousembodiments in FIGS. 28A to 28C. FIGS. 29A and 29B illustrate anexemplary operation using the speculum 2830.

One or more of the components, processes, features, and/or functionsillustrated in the figures may be rearranged and/or combined into asingle component, block, feature or function or embodied in severalcomponents, steps, or functions. Additional elements, components,processes, and/or functions may also be added without departing from thedisclosure. The apparatus, devices, and/or components illustrated in theFigures may be configured to perform one or more of the methods,features, or processes described in the Figures. The algorithmsdescribed herein may also be efficiently implemented in software and/orembedded in hardware.

Note that the aspects of the present disclosure may be described hereinas a process that is depicted as a flowchart, a flow diagram, astructure diagram, or a block diagram. Although a flowchart may describethe operations as a sequential process, many of the operations can beperformed in parallel or concurrently. In addition, the order of theoperations may be re-arranged. A process is terminated when itsoperations are completed. A process may correspond to a method, afunction, a procedure, a subroutine, a subprogram, etc. When a processcorresponds to a function, its termination corresponds to a return ofthe function to the calling function or the main function.

The enablements described above are considered novel over the prior artand are considered critical to the operation of at least one aspect ofthe disclosure and to the achievement of the above described objectives.The words used in this specification to describe the instant embodimentsare to be understood not only in the sense of their commonly definedmeanings, but to include by special definition in this specification:structure, material or acts beyond the scope of the commonly definedmeanings. Thus, if an element can be understood in the context of thisspecification as including more than one meaning, then its use must beunderstood as being generic to all possible meanings supported by thespecification and by the word or words describing the element.

The definitions of the words or drawing elements described above aremeant to include not only the combination of elements which areliterally set forth, but all equivalent structure, material or acts forperforming substantially the same function in substantially the same wayto obtain substantially the same result. In this sense it is thereforecontemplated that an equivalent substitution of two or more elements maybe made for any one of the elements described and its variousembodiments or that a single element may be substituted for two or moreelements in a claim.

Changes from the claimed subject matter as viewed by a person withordinary skill in the art, now known or later devised, are expresslycontemplated as being equivalents within the scope intended and itsvarious embodiments. Therefore, obvious substitutions now or later knownto one with ordinary skill in the art are defined to be within the scopeof the defined elements. This disclosure is thus meant to be understoodto include what is specifically illustrated and described above, what isconceptually equivalent, what can be obviously substituted, and alsowhat incorporates the essential ideas.

In the foregoing description and in the figures, like elements areidentified with like reference numerals. The use of “e.g.,” “etc.” and“or” indicates non-exclusive alternatives without limitation, unlessotherwise noted. The use of “including” or “includes” means “including,but not limited to,” or “includes, but not limited to,” unless otherwisenoted.

As used above, the term “and/or” placed between a first entity and asecond entity means one of (1) the first entity, (2) the second entity,and (3) the first entity and the second entity. Multiple entities listedwith “and/or” should be construed in the same manner, i.e., “one ormore” of the entities so conjoined. Other entities may optionally bepresent other than the entities specifically identified by the “and/or”clause, whether related or unrelated to those entities specificallyidentified. Thus, as a non-limiting example, a reference to “A and/orB”, when used in conjunction with open-ended language such as“comprising” can refer, in one embodiment, to A only (optionallyincluding entities other than B); in another embodiment, to B only(optionally including entities other than A); in yet another embodiment,to both A and B (optionally including other entities). These entitiesmay refer to elements, actions, structures, processes, operations,values, and the like.

It should be noted that where a discrete value or range of values is setforth herein (e.g., 5, 6, 10, 100, etc.), it is noted that the value orrange of values may be claimed more broadly than as a discrete number orrange of numbers, unless indicated otherwise. Any discrete valuesmentioned herein are merely provided as examples.

Terms as used above may have the following definitions.

Cornea and sclera tissues have collagen building blocks, where most ofthe sclera and cornea are primarily connective tissue. Collagen is madeup of 3 single strands of alpha and/or beta chains to form a triplehelix. Collagen fibrils are 25-230 nm in diameter and are arranged intobundles of fibrils that are highly disorganized and variable in size inthe scleral stroma, and very organized and uniform in size in thecorneal stroma. Type 1 is the most common collagen found in the corneaand sclera. The random arrangement and the amount of interweaving in thescleral stroma probably contribute to strength and flexibility of theeye.

The intertwined helices in a collage molecule have non-helical portionson the ends of the strand. The individual molecules from naturallinkages, creating long assemblies of parallel molecules that are thecollagen fibrils. The structure of collagen fibrils is created throughintermolecular cross-linking.

The collagen in the cornea and sclera is associated w/ polysaccharidemolecules called glycosaminoglycans (GAGs). A proteoglycan is a coreprotein to which many GAGs are attached, and they form a matrix aroundthe collagen fibrils. The dominant GAGs in the cornea and sclera aredermatan sulfate and keratan sulfate. The collagen fibrils in the corneaand sclera are then surrounded by and embedded in proteoglycans.

GAGs are rather large molecules. They also have a very negative chargeand, therefore, attract positively charged molecules such as sodium.Sodium comes along with water, so tissues with large amounts of GAGswill take up considerable water if left to their own devices. Thecombination of H₂O creates a gel around the collagen fibrils creatingthe ground substance. The corneal stroma has a higher affinity forwater, whereas the cornea has very narrow limits because it must remaintransparent. In cornea spacing of collagen is key to its transparency.Water content needs to be maintained at a steady level to keep spacingof collagen regular.

In general, a sclera functions to maintain the shape of the eye andresists deforming forces both internal (IOP) and external. The scleraalso provides attachment points for extraocular muscles and the opticnerve. The opacity of the sclera is due to many factors including thenumber of GAG's (glycosaminoglycans-complex sugars that attachcovalently to collagen, the amount of water present, and the size anddistribution of the collagen fibrils.

The sclera has only 25% of the total GAG's that are present in thecornea. Because the GAG's attract water, the sclera is less hydratedthan the cornea (but not 75% less; due to several structures thatcarefully maintain a lower hydration level in the cornea). The largevariation in fibril size and the irregular spacing between scleralcomponents leads to light scattering and opacity. The color of thesclera is white when healthy, but can discolor over time or due toillness (e.g. hepatitis). Internally, the sclera merges with thechoroidal tissue in the suprachoroid layer. The innermost scleral layeris called the lamina fusca.

The sclera contains a number of holes where structures pass through orinterrupt the expansion of the sclera. At the posterior pole of the eyethe optic nerve passes through the posterior scleral layer. This area isbridged by a network of scleral tissue called the lamina cribosa. Thelamina cribosa is the weakest part of the sclera. Elevated IOP couldlead to a bulging out at the optic nerve and subsequent tissue damage.The scleral blood supply is very limited, the tissue is largelyavascular. It contains no capillary beds, only a few small branches fromthe episclera and choroid, and branches of the long posterior ciliaryarteries. Scleral thickness varies from 1.0 mm at the posterior pole to0.3 mm behind rectus muscle insertions. The sclera covers ˜5/6 of theentire eye (about 85%).

The sclera consists of 3 layers: (1) episclera, consists of loosevascularized connective tissue. Branches of the anterior ciliaryarteries form a capillary network anterior to the rectus muscleinsertions. Surrounds the peripheral cornea and is physically linked toTenon's capsule (see Orbit study guide) by connective tissue strands.The sclera thins towards the back of the eye. (2) scleral stroma thickdense connective tissue layer that is continuous with the corneal stromaat the limbus. (3) lamina fusca refers to the few pigmented cells thatremain adherent to sclera after removal of choroids.

Tear layer consists of three layers that together are 7 μm thick. Theouter or most anterior layer (1) is a lipid layer, the middle layer (2)is an aqueous layer that originates from the lacrimal gland. The mucouslayer (3) is in contact with squamous cells (posterior layer).

The cornea functions as the eye's primary refractive element. Mostimportant feature is transparency. The cornea generally comprises about⅙ of the outer layer of the eye. Radius of curvature of ˜8 mm; overallthe cornea is 0.52-0.53 mm thick at the center and 0.71 mm at theperiphery. Posterior side (inner surface) of cornea has smaller radiusof curvature than anterior.

The cornea is the major refractive component of the eye contributingover 40 diopters. It is avascular and transparent transmitting lightvery well. The anterior portion of the cornea is covered with tear film(see above). Optical zone is the circular region of the cornea that is 4mm around the corneal apex. Central radius of curvature and refractivepower: Air/tear interface+43.6 D; Tear/cornea+5.3 D; Cornea/aqueous—5.8D; total central refractive power=43.1 D.

The cornea consists of five layers. From anterior to posterior theyare: 1) Epithelial; 2) bowman's; 3) stroma; 4) Decemet's; 5)endothelium.

Epithelial layer is the first corneal layer and most complex. Theepithelial cell layer is made up of ˜6-8 rows of cells. The epitheliallayer is about 50 μm thick. The entire cornea is about 500-700 microns(μm) thick (0.5 to 0.7 mm). Surface layer (anterior) consists ofsquamous cells that are non-pigmented and have a flattened appearance.The surface of these cells consists of many microvilli that serve toincrease the surface area and stabilize the tear film ‘layer.” Thesquamous cells are connected through tight junctions i.e. ZonulaeOccludens. This creates an effective barrier to exclude foreign materialthat might cause damage. As the surface cells get older theirattachments are lost and the cell is sloughed off in the tear film. Newcells migrate outward from the more internal rows of epithelial cells(bowman's) toward the tear film layer.

The cornea epithelium is subdivided into 3 parts: 1) The squamous celllayers at the surface of the cornea, 2) wing cells that have anappearance of a wing, and 3) columnar basal cells. All the 3 cell typesoriginally derive from the columnar basal cells. So, cells arecontinually being renewed along the basal surface and will ultimately(in about 10 days) turnover an entire new cell layer. Basal cellscommunicate through gap junctions. The middle layer of wing cells is 2-3layers thick. These cells are polyhedral and have convex anteriorsurfaces and concave posterior surfaces. The most posterior cell layerconsists of a single row of columnar basal cells. Cells transform fromcolumnar to cuboidal to squamous. [Programmed cell death is calledapoptosis. This process occurs throughout the body including cornealepithelium cells.] The cells are connected to adjacent cells bydesmosomes and the basement membrane by hemidesmosomes. The basementmembrane (Bowman's) is formed with secretions from the basal epithelialcells. Newly born epithelial cells are formed at the corneal peripheryand then they migrate toward the center of the cornea. There are 325,000nerve endings in epithelial layer of the cornea. These nerve endingsarise from about 2000 nerves which arise from the medial and laterallong ciliary nerves.

Bowman's layer (formerly Bowman's membrane) is the second corneal layer.This layer of cornea is about 10 μm thick. It is a dense, acellularfibrous sheet of interwoven collagen fibers that are randomly arranged.Fibrils are 20-25 μm in diameter. Bowman's layer is a transition layerbetween the basal epithelium and the stroma. This layer is produced bythe epithelium; It does regenerate, but very slowly. Corneal nerves passthrough the layer losing their Schwann cell covering and passing intooverlying epithelium as unmyelinated fibers. The Bowman's layer ends atthe corneal periphery.

The corneal stroma layer is the third layer, also known as substantiapropria. It is 500 to 700 microns thick representing about 90% of thetotal cornea thickness. It is comprised of collagen fibrils andfibroblasts. The fibroblasts in the corneal stroma are often calledkeratocytes [old name, corneal corpuscles] and are specializedfibroblasts that produce collagen fibrils during development andmaintain the connective tissue in the mature eye. Collagen fibrils ofthe cornea are 25-35 nm in diameter and are grouped into flat bundlescalled lamellae. There are 200-300 lamellae distributed throughout thecorneal stroma. All the lamellae run parallel to the surface of thecornea. These stacked fibers account for 90% of the thickness and volumeof the cornea. Adjacent lamellae lie at angles to one another; eachlamellae extends across the entire cornea; each fibril runs from limbusto limbus. In the anterior 1/3 of stroma lamellae are 5-30 μm wide and0.2-1.2 μm thick. Posterior 2/3 of the stroma is more regular and larger(100-200 μm). In the innermost layer, adjacent to the next corneal layerDescemet's membrane the collagen fibrils interlace to form a dense butthin collagenous sheet which contributes to the maintenance of theattachment between the stroma & Descemet's membrane. Keratocytes in thestroma produce fibrils that make up the lamellae. In between the fibrilsis the ground substance that contains proteoglycans (protein with thecarbohydrate glycosaminoglycan (GAG). The GAGs are hydrophilicnegatively charged that are located around specific sites around eachcollagen fibril. The hydrophilic nature of the GAGs serves to keep thestroma well hydrated which helps to maintain the spatial arrangement ofthe fibrils. Corneal hydration and the regular arrangement of thefibrils contributes to corneal transparency. So, proper hydration iscritical to maintain transparency. Proper hydration is maintained by theactions of the epithelium and endothelium to maintain a balance(primarily by pumping water out of the cornea).

The fourth corneal layer is Descemet's membrane layer. Its function isas a structure and tough resistant barrier to perforation of the cornea.Secreted by endothelium. It has 5 types of collagen with Type VIIIdominant. It is considered to be the basement membrane of theendothelium. The layer is constitutively adding new material, so itbecomes thicker with age; it is approximately 10 microns thick. It hasan anterior portion that exhibits a banded appearance like a latticeworkof collagen fibrils. The posterior of Descemet's membrane is non-bandedand is secreted by the endothelial cells throughout life.

Some terms may have definitions that vary in part or wholly from thisdocument. For example, constrict has been defined to mean: to makenarrow or draw together <constrict the pupil of the eye>; to subject (asa body part) to compression <constrict a nerve>; to become constricted;to become tighter and narrower, or to make something become tighter andnarrower, e.g. the drug causes the blood vessels to constrict.

Contracture has been variously defined to mean: a permanent shortening(as of muscle, tendon, or scar tissue) producing deformity ordistortion; to shorten; to become reduced in size; in the case ofmuscle, either to shorten or to undergo an increase in tension; toacquire by contagion or infection; an explicit bilateral commitment bypsychotherapist and patient to a defined course of action to attain thegoal of the psychotherapy; To straighten a limb, to diminish orextinguish the angle formed by flexion; to place the distal segment of alimb in such a position that its axis is continuous with that of theproximal segment.

Extension has been defined to mean: additional piece, a piece that hasbeen or can be added, or that can be pulled out, to enlarge or lengthensomething.

Expansion has been defined in various circumstances as meaning: the actor process of expanding; the quality or state of being expanded; toincrease in size, number or importance, or to make something increase inthis way, process of becoming enlarged: the process of increasing, orincreasing something, in size, extent, scope, or number.

Perforate has been defined in various forms to mean: to make a hole orholes in something; pierced with one or more holes.

In diagnostic or therapeutic radiology, a plate made of one or moremetals such as aluminum and copper which, placed in the x- or gamma raybeam, permits passage of a greater proportion of higher-energy radiationand attenuation of lower-energy and less desirable radiation, raisingthe average energy or hardening the beam. A device used inspectrophotometric analysis to isolate a segment of the spectrum. Amathematical algorithm applied to image data for the purpose ofenhancing image quality, usually by suppression or enhancement of highspatial frequencies. A passive electronic circuit or device thatselectively permits the passage of certain electrical signals. A deviceplaced in the inferior vena cava to prevent pulmonary embolism from lowextremity clot. There are many variants.

Puncture is defined as to make a hole or holes in something; make holesfor tearing: to make a line of small holes in paper to make tearing iteasier; penetrate something: penetrate or pass through something;biology with small holes: dotted with small holes; biology withtransparent spots: dotted with transparent spots.

Perforate: to drill, bore, drill, drive, hole, honeycomb, penetrate,permeate, pierce, pit, probe, punch, puncture, slit, stab, burrow,gouge, mine, penetrate, perforate, pierce, pit, prick, punch, puncture,ream, riddle, sink, tunnel.

Crenellate has been defined as: to indent; to notch; as, a crenelatedleaf; having repeated square indentations like those in a battlement; “acrenelated molding.”

Compression: reduction in size, the reduction of the volume or mass ofsomething by applying pressure, or the state of having been treated inthis way.

Decompression: pressure decrease: a decrease in surrounding or inherentpressure, especially the controlled decrease in pressure that diversundergo to prevent decompression sickness; to reduce pressure in organ:a surgical procedure to reduce pressure in an organ or part of the bodycaused, for example, by fluid on the brain, or to reduce the pressure oftissues on a nerve; computing data expansion: the expansion to full sizeof compressed computer data.

Flexible: susceptible to being led or directed; “fictile masses ofpeople ripe for propaganda” able to adjust readily to differentconditions; “an adaptable person”; “a flexible personality”; “an elasticclause in a contract” [elastic, flexible, pliant]; “a flexible wire”; “apliant young tree” [bendable, pliant]; [ductile, malleable, pliant,tensile, tractile]

Pliable: capable of being bent or flexed or twisted without breaking;capable of being shaped or bent or drawn out; “ductile copper”;“malleable metals such as gold”; “they soaked the leather to made itpliable”; “pliant molten glass”; “made of highly tensile steel alloy”.

Diaphragm: muscular membranous partition separating the abdominal andthoracic cavities and functioning in respiration; also called midriff; athin disk, especially in a microphone or telephone receiver, thatvibrates in response to sound waves to produce electric signals, or thatvibrates in response to electric signals to produce sound waves; amusculo-membranous partition separating the abdominal and thoraciccavities and functioning in respiration.

Pore as used herein means minute opening in tissue, as in the skin of ahuman or an animal, serving for example as an outlet for perspiration.

Nuclear pores Openings in the membrane of a cell's nuclear envelope thatallow the exchange of materials between the nucleus and the cytoplasm.

Nucleic acids can be defined as polymers composed of nucleotides; e.g.,DNA and RNA.

What is claimed is:
 1. A system for delivering microporation medicaltreatments to improve biomechanics, the system comprising: a laser forgenerating a beam of laser radiation on a treatment-axis not alignedwith a patient's visual-axis, operable for use in subsurface ablativemedical treatments to create an array pattern of micropores thatimproves biomechanics; a housing; a controller within the housing, incommunication with the laser and operable to control dosimetry of thebeam of laser radiation in application to a target tissue; a lensoperable to focus the beam of laser radiation onto a target tissue; anautomated off-axis subsurface anatomy tracking, measuring, and avoidancesystem; and wherein the array pattern of micropores is at least one of aradial pattern, a spiral pattern, a phyllotactic pattern, or anasymmetric pattern.
 2. The system of claim 1, wherein the array patternof micropores is a spiral pattern of an Archimedean spiral, a Eulerspiral, a Fermat's spiral, a hyperbolic spiral, a lituus, a logarithmicspiral, a Fibonacci spiral, a golden spiral, or combinations thereof. 3.The system of claim 1, wherein the array pattern of micropores has acontrolled asymmetry.
 4. The system of claim 3, wherein the controlledasymmetry is an at least partial rotational asymmetry about the centerof the array pattern.
 5. The system of claim 1, wherein the arraypattern of micropores has a controlled symmetry.
 6. The system of claim5, wherein the controlled symmetry is at least partial rotationalsymmetry about the center of the array pattern.
 7. The system of claim1, wherein the array pattern has a number of clockwise spirals and anumber of counter-clock wise spirals.
 8. The system of claim 7, whereinthe number of clockwise spirals and the number of counterclockwisespirals are Fibonacci numbers or multiples of Fibonacci numbers.
 9. Thesystem of claim 7, wherein the number of clockwise spirals and thenumber of counterclockwise spirals are in a ratio that converges on thegolden ratio.
 10. The system of claim 4, wherein the at least partialrotational asymmetry extends to at least 51 percent of the micropores ofthe array pattern.
 11. The system of claim 4, wherein the at leastpartial rotational asymmetry extends to at least 20 micropores of thearray pattern.
 12. The system of claim 6, wherein the at least partialrotational symmetry extends to at least 51 percent of the micropores ofthe pattern.
 13. The system of claim 6, wherein the at least partialrotational symmetry extends to at least 20 micropores of the arraypattern.
 14. The system of claim 1, wherein the array pattern ofmicropores has a random asymmetry.
 15. The system of claim 1, whereinthe array pattern of micropores has a random symmetry.
 16. A method ofdelivering microporation medical treatments to improve biomechanicscomprising: generating, by a laser, a treatment beam on a treatment-axisnot aligned with a patient's visual-axis in a subsurface ablativemedical treatment to create an array of micropores that improvesbiomechanics; controlling, by a controller in electrical communicationwith the laser, dosimetry of the treatment beam in application to atarget tissue; focusing, by a lens, the treatment beam onto the targettissue; monitoring, by an automated off-axis subsurface anatomytracking, measuring, and avoidance system, an eye position forapplication of the treatment beam; and wherein the array pattern ofmicropores is at least one of a radial pattern, a spiral pattern, aphyllotactic pattern, or an asymmetric pattern.
 17. The method of claim16, wherein the array pattern of micropores is a spiral pattern of anArchimedean spiral, a Euler spiral, a Fermat's spiral, a hyperbolicspiral, a lituus, a logarithmic spiral, a Fibonacci spiral, a goldenspiral, or combinations thereof.
 18. The method of claim 16, wherein thearray pattern of micropores has a controlled asymmetry.
 19. The methodof claim 18, wherein the controlled asymmetry is an at least partialrotational asymmetry about the center of the array pattern.
 20. Themethod of claim 16, wherein the array pattern of micropores has acontrolled symmetry.